Androgen Receptor Modulator Compounds and Methods

ABSTRACT

Provided herein are compounds having a structure selected from among Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) and Formula (VI) that are androgen receptor modulators and/or androgen receptor binding agents. Also disclosed are methods of making and using such compounds, including, but not limited to, using such compounds for treating various conditions.

RELATED APPLICATIONS

Priority is claimed to U.S. provisional patent application Ser. No.60/552,690, filed Mar. 12, 2004, entitled “ANDROGEN RECEPTOR MODULATORCOMPOUNDS AND METHODS.”

For purposes of the U.S. national stage, priority is claimed hereinunder 35 U.S.C. §119(e) to U.S. provisional patent application Ser. No.60/552,690, filed Mar. 12, 2004, entitled “ANDROGEN RECEPTOR MODULATORCOMPOUNDS AND METHODS.” Where permitted, the disclosure of theabove-referenced provisional application is incorporated herein byreference in its entirety.

FIELD

Provided herein are compounds that bind to androgen receptors and/ormodulate activity of androgen receptors, and to methods for making andusing such compounds. Also provided are compositions containing suchcompounds and methods for making and using such compositions.

BACKGROUND

Certain intracellular receptors (IRs) have been shown to regulatetranscription of certain genes. See e.g., R. M. Evans, Science, 240, 889(1988). Certain of such IRs are steroid receptors, such as androgenreceptors, glucocorticoid receptors, estrogen receptors,mineralocorticoid receptors, and progesterone receptors. Gene regulationby such receptors typically involves binding of an IR by a ligand.

In certain instances, a ligand binds to an IR, forming a receptor/ligandcomplex. Such a receptor/ligand complex may then translocate to thenucleus of a cell, where it may bind to the DNA of one or more generegulatory regions. Once bound to the DNA of a particular generegulatory region, a receptor/ligand complex may modulate the productionof the protein encoded by that particular gene. In certain instances, anandrogen receptor/ligand complex regulates expression of certainproteins. In certain instances, an androgen receptor/ligand complex mayinteract directly with the DNA of a particular gene regulatory region.In certain instances, an androgen receptor/ligand complex may interactwith other transcription factors, such as activator protein-1 (AP-1) ornuclear factor κB (NFκB). In certain instances, such interactions resultin modulation of transcriptional activation.

SUMMARY

Compounds for use in compositions and methods for modulating theactivity of androgen receptor are provided. In one embodiment, thecompounds provided herein are agonists of androgen receptor. In anotherembodiment, the compounds provided herein are antagonists of androgenreceptor.

In certain embodiments, provided herein are compounds having a structureselected from among Formula I, Formula II, Formula III, Formula IV,Formula V and Formula VI:

wherein:

R¹ and R² are each independently selected from hydrogen, F, Cl, Br, I,OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, COR^(A), CO₂R^(A), CONR^(A)R^(B), SOR^(A), SO₂R^(A), andSO₂NR^(A)R^(B), NHCOR^(A), and NHCONR^(A)R^(B), provided that at leastone of R¹ and R² is not hydrogen;

R³, R^(3a), R⁴, and R⁵ are each independently selected from hydrogen, F,Cl, OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl;

wherein if R¹ is NO₂ and R^(3a) is F, then at least one of R² and R⁴ andR⁵ is not hydrogen; and wherein if R¹ is NO₂ and R³ is F, then Z is notO;

R⁶, R⁷, R¹⁰, and R¹¹ are each independently selected from hydrogen, anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl, an optionally substituted C₂-C₆heterohaloalkenyl, an optionally substituted C₂-C₆ heterohaloalkynyl, anoptionally substituted C₂-C₆ alkynyl, and an optionally substitutedC₂-C₆ alkenyl;

R^(6a) and R^(7a) are each independently selected from hydrogen, anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl, an optionally substituted C₂-C₆heterohaloalkenyl, an optionally substituted C₂-C₆ heterohaloalkynyl, anoptionally substituted C₂-C₆ alkynyl, and an optionally substitutedC₂-C₆ alkenyl; or R^(6a) and R^(7a) together form a carbonyl;

R⁸ and R⁹ are each independently selected from hydrogen, an optionallysubstituted C₁-C₈ alkyl, an optionally substituted C₂-C₈ alkenyl, anoptionally substituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, C₁-C₈ heteroalkyl, an optionally substituted C₂-C₈heteroalkenyl, an optionally substituted C₂-C₈ alkynyl, an optionallysubstituted C₂-C₈ haloalkynyl, an optionally substituted C₂-C₈heteroalkynyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₁-C₆ heterohaloalkenyl, an optionallysubstituted C₁-C₆ heterohaloalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), COR^(A), CO₂R^(A) and (CH₂)_(m)R^(C);

R¹² and R¹³ are each independently selected from hydrogen, F, Cl,OR^(A), NR^(A)R^(B), SR^(A), an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆heteroalkyl, an optionally substituted C₂-C₆ alkynyl, an optionallysubstituted C₁-C₆ heterohaloalkyl, an optionally substituted C₁-C₆heterohaloalkenyl, an optionally substituted C₁-C₆ heterohaloalkynyl, anoptionally substituted C₂-C₆ alkenyl, and (CH₂)_(m)R^(C); R¹⁴ and R¹⁵are each independently selected from hydrogen, F, Cl, Br, I, OR^(A),SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B), COR^(A), CO₂R^(A),CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B);

R¹⁶ and R¹⁷ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl;

R¹⁸ and R¹⁹ are each independently selected from hydrogen, F, Cl, Br, I,OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B), COR^(A), CO₂R^(A),CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B);

R²⁰ and R²¹ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl; wherein if R¹⁸ is NO₂ and X is O, then atleast one of R¹⁹, R²⁰, and R²¹ is not hydrogen, and wherein if R¹⁹ isNO₂ and X is C, then at least one of R¹⁸, R²⁰, and R²¹ is not hydrogen;

R²² is selected from hydrogen, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, COR⁶, CO₂R^(A), CONR^(A)R^(B), SO₂R^(A), an optionallysubstituted aryl, an optionally substituted heteroaryl,CH₂CH(R^(D))OR^(A), CH₂CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C), whereinthe optionally substituted aryl or optionally substituted heteroaryl isoptionally substituted with a substituent selected from F, Cl, Br, I,CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A), SO₂R^(A), an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, andan optionally substituted C₁-C₄ heteroalkyl;

R²³ and R²⁴ are each independently selected from hydrogen, an optionallysubstituted C₁-C₈ alkyl, an optionally substituted C₂-C₈ alkenyl, anoptionally substituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, an optionally substituted C₁-C₈ heteroalkyl, an optionallysubstituted C₂-C₈ heteroalkenyl, an optionally substituted C₂-C₈alkynyl, an optionally substituted C₂-C₈ haloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C); or R²³ and R²⁴ together form acarbonyl group, provided that if R¹⁸ is NO₂ and X is NH, then R²³ andR²⁴ do not together form a carbonyl group; or

R²² and R²³ are optionally linked to form a ring; or

R²³ and R²⁵ are optionally linked to form a ring;

X is selected from O, S, CR^(A)R^(B), NR^(D), and a bond;

wherein if X is CR^(A)R^(B) or a bond, then R²⁵ and R²⁶ are eachindependently selected from a halogen, OR^(A), NR^(A)R^(B), hydrogen, anoptionally substituted C₁-C₈ alkyl, an optionally substituted C₂-C₈alkenyl, an optionally substituted C₁-C₈ haloalkyl, an optionallysubstituted C₂-C₈ haloalkenyl, an optionally substituted C₁-C₈heteroalkyl, an optionally substituted C₂-C₈ heteroalkenyl, anoptionally substituted C₂-C₈ alkynyl, an optionally substituted C₂-C₈haloalkynyl, an optionally substituted C₂-C₈ heteroalkynyl, anoptionally substituted aryl, an optionally substituted heteroaryl, and(CH₂)_(m)R^(C); or R²⁵ and R²⁶ together form a carbonyl group;

and wherein if X is O, S, or NR^(D), then R²⁵ and R²⁶ are eachindependently selected from hydrogen, an optionally substituted C₁-C₈alkyl, an optionally substituted C₂-C₈ alkenyl, an optionallysubstituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, an optionally substituted C₁-C₈ heteroalkyl, an optionallysubstituted C₂-C₈ heteroalkenyl, an optionally substituted C₂-C₈alkynyl, an optionally substituted C₂-C₈ haloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, and (CH₂)_(m)R^(C); or R²⁵ and R²⁶together form a carbonyl group;

R²⁵ is selected from a halogen, OR^(A), NR^(A)R^(B), hydrogen, anoptionally substituted C₁-C₈ alkyl, an optionally substituted C₂-C₈alkenyl, an optionally substituted C₁-C₈ haloalkyl, an optionallysubstituted C₂-C₈ haloalkenyl, an optionally substituted C₁-C₈heteroalkyl, an optionally substituted C₂-C₈ heteroalkenyl, anoptionally substituted C₂-C₈ alkynyl, an optionally substituted C₂-C₈haloalkynyl, an optionally substituted C₂-C₈ heterohaloalkenyl, anoptionally substituted C₂-C₈ heterohaloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, and (CH₂)_(m)R^(C);

R^(A) and R^(B) are each independently selected from hydrogen, anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, and an optionally substituted C₁-C₄ heteroalkyl;

R^(C) is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl that is optionally with a substituent selectedfrom F, Cl, Br, I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A),SO₂R^(A), an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl;

R^(D) is selected from hydrogen, an optionally substituted C₁-C₄ alkyl,an optionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl;

Z is selected from O, S, CR^(A)R^(B), and NR^(D);

n is 0, 1, or 2; and

m is 1 or 2.

Also of interest are any pharmaceutically-acceptable derivatives,including salts, esters, enol ethers, enol esters, solvates, hydratesand prodrugs of the compounds described herein.Pharmaceutically-acceptable salts, include, but are not limited to,amine salts, such as but not limited to N,N′-dibenzylethylene-diamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc, aluminum, and other metal salts, such as but not limited tosodium hydrogen phosphate and disodium phosphate; and also including,but not limited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates.

In certain embodiments, provided herein is a compound selected from: (a)N,N′-bis(2,2,2-trifluoroethyl)-3-methyl-4-nitroaniline;N,N′-bis(2,2,2-trifluoroethyl)-4-nitroaniline;5-(2,2,2-trifluoroethyl)amino-2-bromobenzotrifluoride;4-N,N′-bis(2,2,2-trifluoroethyl)amino-2-trifluoromethylbenzonitrile;(R)—N-4-nitrophenyl-5-(dimethyl-tert-butylsilyloxymethyl)-2-pyrrolidone;(R)—N-4-nitrophenyl-5-hydroxymethyl-2-pyrrolidone;(R)—N-(4-nitro-3-trifluoromethylphenyl)-2-dimethyl-tert-butylsilyloxymethylpyrrolidine;(R)—N-(4-nitro-3-trifluoromethylphenyl)-2-hydroxymethylpyrrolidine;(R)—N-(4-nitrophenyl)-2-hydroxymethylpyrrolidine;(R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine;N-(3-Trifluoromethyl-4-nitrophenyl)-2-(R)-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;N-(3-Trifluoromethyl-4-nitrophenyl)-2-(R)-(1-(R)—hydroxy-2,2,2-trifluoroethyl)pyrrolidine;(S)—N-(4-nitrophenyl)-2-hydroxymethylpyrrolidine;N-(4-nitrophenyl)-2-(R)-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;N-(4-nitrophenyl)-2-(R)-(1-(R)-hydroxy-2,2,2-trifluoroethyl);N-(4-nitrophenyl)-2-(S)-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;andN-(4-nitrophenyl)-2-(S)-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;and (b) a pharmaceutically acceptable salt, ester, amide, or prodrugthereof.

In certain embodiments, provided herein are methods for modulating anactivity of an androgen receptor by contacting an androgen receptor withat least one compound provided herein. In certain such embodiments, theandrogen receptor is in a cell.

In certain embodiments, the provided herein are methods for identifyinga compound that is capable of modulating an activity of an androgenreceptor, by contacting a cell expressing an androgen receptor with acompound provided herein; and monitoring an effect of the compound uponthe cell.

In certain embodiments, provided herein are methods for treating apatient by administering to the patient a compound provided herein. Incertain embodiments, the methods provided herein are for maintenance ofmuscle strength and function (e.g., in the elderly); reversal orprevention of frailty or age-related functional decline (“ARFD”) in theelderly (e.g., sarcopenia); treatment of catabolic side effects ofglucocorticoids; prevention and/or treatment of reduced bone mass,density or growth (e.g., osteoporosis and osteopenia); treatment ofchronic fatigue syndrome (CFS); chronic myalgia; treatment of acutefatigue syndrome and muscle loss following elective surgery (e.g.,post-surgical rehabilitation); accelerating of wound healing;accelerating bone fracture repair (such as accelerating the recovery ofhip fracture patients); accelerating healing of complicated fractures,e.g. distraction osteogenesis; in joint replacement; prevention ofpost-surgical adhesion formation; acceleration of tooth repair orgrowth; maintenance of sensory function (e.g., hearing, sight,olefaction and taste); treatment of periodontal disease; treatment ofwasting secondary to fractures and wasting in connection with chronicobstructive pulmonary disease (COPD), chronic liver disease, AIDS,weightlessness, cancer cachexia, burn and trauma recovery, chroniccatabolic state (e.g., coma), eating disorders (e.g., anorexia) andchemotherapy; treatment of cardiomyopathy; treatment ofthrombocytopenia; treatment of growth retardation in connection withCrohn's disease; treatment of short bowel syndrome; treatment ofirritable bowel syndrome; treatment of inflammatory bowel disease;treatment of Crohn's disease and ulcerative colits; treatment ofcomplications associated with transplantation; treatment ofphysiological short stature including growth hormone deficient childrenand short stature associated with chronic illness; treatment of obesityand growth retardation associated with obesity; treatment of anorexia(e.g., associated with cachexia or aging); treatment of hypercortisolismand Cushing's syndrome; Paget's disease; treatment of osteoarthritis;induction of pulsatile growth hormone release; treatment ofosteochondrodysplasias; treatment of depression, nervousness,irritability and stress; treatment of reduced mental energy and lowself-esteem (e.g., motivation/assertiveness); improvement of cognitivefunction (e.g., the treatment of dementia, including Alzheimer's diseaseand short term memory loss); treatment of catabolism in connection withpulmonary dysfunction and ventilator dependency; treatment of cardiacdysfunction (e.g., associated with valvular disease, myocardialinfarction, cardiac hypertrophy or congestive heart failure); loweringblood pressure; protection against ventricular dysfunction or preventionof reperfusion events; treatment of adults in chronic dialysis; reversalor slowing of the catabolic state of aging; attenuation or reversal ofprotein catabolic responses following trauma (e.g., reversal of thecatabolic state associated with surgery, congestive heart failure,cardiac myopathy, burns, cancer, COPD etc.); reducing cachexia andprotein loss due to chronic illness such as cancer or AIDS; treatment ofhyperinsulinemia including nesidioblastosis; treatment ofimmunosuppressed patients; treatment of wasting in connection withmultiple sclerosis or other neurodegenerative disorders; promotion ofmyelin repair; maintenance of skin thickness; treatment of metabolichomeostasis and renal homeostasis (e.g., in the frail elderly);stimulation of osteoblasts, bone remodeling and cartilage growth;regulation of food intake; treatment of insulin resistance, includingNIDDM, in mammals (e.g., humans); treatment of insulin resistance in theheart; improvement of sleep quality and correction of the relativehyposomatotropism of senescence due to high increase in REM sleep and adecrease in REM latency; treatment of hypothermia; treatment ofcongestive heart failure; treatment of lipodystrophy (e.g., in patientstaking HIV or AIDS therapies such as protease inhibitors); treatment ofmuscular atrophy (e.g., due to physical inactivity, bed rest or reducedweight-bearing conditions); treatment of musculoskeletal impairment(e.g., in the elderly); improvement of the overall pulmonary function;treatment of sleep disorders; and the treatment of the catabolic stateof prolonged critical illness; treatment of hirsutism, acne, seborrhea,androgenic alopecia, anemia, hyperpilosity, benign prostate hypertrophy,adenomas and neoplasies of the prostate (e.g., advanced metastaticprostate cancer) and malignant tumor cells containing the androgenreceptor, such as is the case for breast, brain, skin, ovarian, bladder,lymphatic, liver and kidney cancers; cancers of the skin, pancreas,endometrium, lung and colon; osteosarcoma; hypercalcemia of malignancy;metastatic bone disease; treatment of spermatogenesis, endometriosis andpolycystic ovary syndrome; conteracting preeclampsia, eclampsia ofpregnancy and preterm labor; treatment of premenstural syndrome;treatment of vaginal dryness; age related decreased testosterone levelsin men, male menopause, hypogonadism, male hormone replacement, male andfemale sexual dysfunction (e.g., erectile dysfunction, decreased sexdrive, sexual well-being, decreased libido), male and femalecontraception, hair loss, Reaven's Syndrome and the enhancement of boneand muscle performance/strength.

In certain of such embodiments, the patient has a condition selectedfrom acne, male-pattern baldness, wasting diseases, hirsutism,hypogonadism, osteoporoses, infertility, impotence, and cancer.

In certain embodiments, the methods provided herein are for stimulatinghematopoiesis. In certain embodiments, the methods provided herein arefor contraception. In certain embodiments, the methods provided hereinare for improving athletic performance.

In certain embodiments, the compounds provided herein are selectiveandrogen receptor modulators. In certain embodiments, the compoundsprovided herein are selective androgen receptor agonists. In certainembodiments, the compounds provided herein are selective androgenreceptor antagonists. In certain embodiments, the compounds providedherein are androgen receptor partial agonists. In certain embodiments,the compounds provided herein are selective androgen receptor bindingcompounds.

In certain embodiments, provided herein are methods for modulating atleast one activity of an androgen receptor. Certain of such methods areeffected by contacting an androgen receptor with one or more compoundsprovided herein.

In certain embodiments, methods are provided for treating a patient byadministering to the patient a compound provided herein. In certainembodiments, the methods provided herein are for treating a conditionincluding, but not limited to, acne, male-pattern baldness, wastingdiseases, hirsutism, hypogonadism, osteoporoses, infertility, impotence,and cancer.

Pharmaceutical compositions formulated for administration by anappropriate route and means containing effective concentrations of oneor more of the compounds provided herein, or pharmaceutically acceptablederivatives thereof, that deliver amounts effective for the treatment,prevention, or amelioration of one or more symptoms of diseases ordisorders that are modulated or otherwise affected by androgen receptoractivity, or in which androgen receptor activity is implicated, are alsoprovided. The effective amounts and concentrations are effective forameliorating any of the symptoms of any of the diseases or disorders.

In certain embodiments, provided herein is a pharmaceutical compositioncontaining: i) a physiologically acceptable carrier, diluent, and/orexcipient; and ii) one or more compounds provided herein.

Articles of manufacture containing packaging material, within thepackaging material a compound or composition, or pharmaceuticallyacceptable derivative thereof, which is effective for modulating theactivity of androgen receptor, or for treatment, prevention oramelioration of one or more symptoms of androgen receptor mediateddiseases or disorders, or diseases or disorders in which androgenreceptor activity is implicated, and a label that indicates that thecompound or composition, or pharmaceutically acceptable derivativethereof, is used for modulating the activity of androgen receptor, orfor treatment, prevention or amelioration of one or more symptoms ofandrogen receptor mediated diseases or disorders, or diseases ordisorders in which androgen receptor activity is implicated, areprovided.

DETAILED DESCRIPTION

A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. All patents, patentapplications, published materials referred to throughout the entiredisclosure herein, unless noted otherwise, are incorporated by referencein their entirety. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Wherereference is made to a URL or other such identifier or address, itunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the subject matter claimed. In thisapplication, the use of the singular includes the plural unlessspecifically stated otherwise. In this application, the use of “or”means “and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as “includes,” and “included,”is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, but not limited to, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference in their entirety for any purpose.

Unless specific definitions are provided, the nomenclatures utilized inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those known in the art.Standard techniques may be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation, and delivery, andtreatment of patients. Standard techniques may be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection). Reactions and purificationtechniques may be performed e.g., using kits according to manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures may be generallyperformed according to conventional methods well known in the art and asdescribed in various general and more specific references that are citedand discussed throughout the present specification. See e.g., Sambrooket al. Molecular Cloning: A Laboratory Manual (2d ed., Cold SpringHarbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which isincorporated herein by reference for any purpose.

As used herein, the term “selective binding compound” refers to acompound that selectively binds to any portion of one or more targetreceptors.

As used herein, the term “selective androgen receptor binding compound”refers to a compound that selectively binds to any portion of anandrogen receptor.

As used herein, the following terms are defined with the followingmeanings, unless explicitly stated otherwise.

As used herein, the term “selective binding compound” refers to acompound that selectively binds to any portion of one or more targetreceptors.

As used herein, the term “selective androgen receptor binding compound”refers to a compound that selectively binds to any portion of anandrogen receptor.

As used herein, the term “selectively binds” refers to the ability of aselective binding compound to bind to a target receptor with greateraffinity than it binds to a non-target receptor. In certain embodiments,specific binding refers to binding to a target with an affinity that isat least 10, 50, 100, 250, 500, 1000 or more times greater than theaffinity for a non-target.

As used herein, the term “target receptor” refers to a molecule or aportion of a receptor capable of being bound by a selective bindingcompound. In certain embodiments, a target receptor is an androgenreceptor.

As used herein, the terms “treating” or “treatment” encompass either orboth responsive and prophylaxis measures, e.g., designed to inhibit ordelay the onset of the disease or disorder, achieve a full or partialreduction of the symptoms or disease state, and/or to alleviate,ameliorate, lessen, or cure the disease or disorder and/or its symptoms.Treatment also encompasses any pharmaceutical use of the compositionsherein, such as use for treating a gluococorticoid mediated diseases ordisorders.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular compound or pharmaceutical compositionrefers to any lessening, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe composition.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator can cause an increaseor decrease in the magnitude of a certain activity of a moleculecompared to the magnitude of the activity in the absence of themodulator. In certain embodiments, a modulator is an inhibitor, whichdecreases the magnitude of one or more activities of a molecule. Incertain embodiments, an inhibitor completely prevents one or moreactivities of a molecule. In certain embodiments, a modulator is anactivator, which increases the magnitude of at least one activity of amolecule. In certain embodiments the presence of a modulator results inan activity that does not occur in the absence of the modulator.

As used herein, the term “selective modulator” refers to a compound thatselectively modulates a target activity.

As used herein, the term “selective androgen receptor modulator” refersto a compound that selectively modulates at least one activityassociated with an androgen receptor.

As used herein, the term “selectively modulates” refers to the abilityof a selective modulator to modulate a target activity to a greaterextent than it modulates a non-target activity. In certain embodimentsthe target activity is selectively modulated by, for example about 2fold up to more than about 500 folds, in some embodiments, about 2, 5,10, 50, 100, 150, 200, 250, 300, 350, 400, 450 or more than 500 folds.

As used herein, the term “target activity” refers to a biologicalactivity capable of being modulated by a selective modulator. Certainexemplary target activities include, but are not limited to, bindingaffinity, signal transduction, enzymatic activity, tumor growth, andinflammation or inflammation-related processes.

As used herein, the term “receptor mediated activity” refers anybiological activity that results, either directly or indirectly, frombinding of a ligand to a receptor.

As used herein, the term “agonist” refers to a compound, the presence ofwhich results in a biological activity of a receptor that is the same asthe biological activity resulting from the presence of a naturallyoccurring ligand for the receptor.

As used herein, the term “partial agonist” refers to a compound thepresence of which results in a biological activity of a receptor that isof the same type as that resulting from the presence of a naturallyoccurring ligand for the receptor, but of a lower magnitude.

As used herein, the term “antagonist” refers to a compound, the presenceof which results in a decrease in the magnitude of a biological activityof a receptor. In certain embodiments, the presence of an antagonistresults in complete inhibition of a biological activity of a receptor.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as modulation of androgen receptor activity, in an assaythat measures such response.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x).

As used herein, the term “alkyl” refers to an aliphatic hydrocarbongroup. An alkyl group can be a “saturated alkyl,” which means that itdoes not contain any alkene or alkyne groups. An alkyl group can be an“unsaturated alkyl,” which means that it contains at least one alkene oralkyne group. An alkyl, whether saturated or unsaturated, can bebranched, straight chain, or cyclic.

In certain embodiments, an alkyl contains 1 to 20 carbon atoms (wheneverit appears herein, a numerical range such as “1 to 20” refers to eachinteger in the given range; e.g., “1 to 20 carbon atoms” means that analkyl group can contain only 1 carbon atom, 2 carbon atoms, 3 carbonatoms, etc., up to and including 20 carbon atoms, although the term“alkyl” also includes instances where no numerical range of carbon atomsis designated).

As used herein, the term “lower alkyl” refers to an alkyl containing 1to 5 carbon atoms. The term “medium alkyl” refers to an alkyl containing5 to 10 carbon atoms. An alkyl can be designated as “C₁-C₄ alkyl” orsimilar designations. By way of example only, “C₁-C₄ alkyl” indicates analkyl having one, two, three, or four carbon atoms, i.e., the alkyl isselected from among methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, and t-butyl. Thus C₁-C₄ includes C₁-C₂ and C₁-C₃alkyl. Alkyls can be substituted or unsubstituted. Alkyls include, butare not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like, each of which can beoptionally substituted.

As used herein, the term “alkenyl” refers to an alkyl group containingat least one carbon-carbon double bond.

As used herein, the term “alkynyl” refers to an alkyl group containingat least one carbon-carbon triple bond.

As used herein, the term “haloalkyl” refers to an alkyl in which atleast one hydrogen atom is replaced with a halogen atom. In certain ofthe embodiments in which two or more hydrogen atom are replaced withhalogen atoms, the halogen atoms are all the same as one another. Incertain of such embodiments, the halogen atoms are not all the same asone another.

As used herein, the term “heteroalkyl” refers to a group containing analkyl and one or more heteroatoms. Certain heteroalkyls are acylalkyls,in which the one or more heteroatoms are within an alkyl chain. Examplesof heteroalkyls include, but are not limited to, CH₃C(═O)CH₂—,CH₃C(═O)CH₂CH₂—, CH₃CH₂C(═O)CH₂CH₂—, CH₃C(═O)CH₂CH₂CH₂—, CH₃OCH₂CH₂—,CH₃NHCH₂—, and the like.

As used herein, the term “heterohaloalkyl” refers to a heteroalkyl inwhich at least one hydrogen atom is replaced with a halogen atom.

As used herein, the term “carbocycle” refers to a group containing acovalently closed ring, wherein each of the atoms forming the ring is acarbon atom. Carbocylic rings can be formed by three, four, five, six,seven, eight, nine, or more than nine carbon atoms. Carbocycles can beoptionally substituted.

As used herein, the term “heterocycle” refers to a group containing acovalently closed ring wherein at least one atom forming the ring is aheteroatom. Heterocyclic rings can be formed by three, four, five, six,seven, eight, nine, or more than nine atoms. Heterocycles can beoptionally substituted. Binding to a heterocycle can be at a heteroatomor via a carbon atom. For example, binding for benzo-fused derivatives,can be via a carbon of the benzenoid ring.

As used herein, the term “heteroatom” refers to an atom other thancarbon or hydrogen. Heteroatoms are typically independently selectedfrom oxygen, sulfur, nitrogen, and phosphorus, but are not limited tothose atoms. In embodiments in which two or more heteroatoms arepresent, the two or more heteroatoms can all be the same as one another,or some or all of the two or more heteroatoms can each be different fromthe others.

As used herein, the term “aromatic” refers to a group containing acovalently closed ring having a delocalized π-electron system. Aromaticrings can be formed by three, four, five, six, seven, eight, nine, ormore than nine atoms. Aromatics can be optionally substituted. Examplesof aromatic groups include, but are not limited to phenyl, naphthalenyl,phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.The term aromatic includes, for example, benzenoid groups, connected viaone of the ring-forming carbon atoms, and optionally carrying one ormore substituents selected from an aryl, a heteroaryl, a cycloalkyl, anon-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro,an alkylamido, an acyl, a C₁-C₆ alkoxy, a C₁-C₆ alkyl, a hydroxyC₁-C₆alkyl, a aminoC₁-C₆ alkyl, a C₁-C₆alkylamino, an alkylsulfenyl, analkylsulfinyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl. Incertain embodiments, an aromatic group is substituted at one or more ofthe para, meta, and/or ortho positions. Examples of aromatic groupscontaining substitutions include, but are not limited to, phenyl,3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl,3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl,3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl,hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl,4-morpholin-4-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl,4-triazolylphenyl, and 4-(2-oxopyrrolidin-1-yl)phenyl.

As used herein, the term “aryl” refers to an aromatic group wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby three, four, five, six, seven, eight, nine, or more than nine carbonatoms. Aryl groups can be optionally substituted.

As used herein, the term “heteroaryl” refers to an aromatic group inwhich at least one atom forming the aromatic ring is a heteroatom.Heteroaryl rings can be formed by three, four, five, six, seven, eight,nine and more than nine atoms. Heteroaryl groups can be optionallysubstituted. Examples of heteroaryl groups include, but are not limitedto, aromatic C₃-C₈ heterocyclic groups containing one oxygen or sulfuratom or up to four nitrogen atoms, or a combination of one oxygen orsulfur atom and up to two nitrogen atoms, and their substituted as wellas benzo- and pyrido-fused derivatives, for example, connected via oneof the ring-forming carbon atoms. In certain embodiments, heteroarylgroups are optionally substituted with one or more substituents,independently selected from halo, hydroxy, amino, cyano, nitro,alkylamido, acyl, C₁-C₆-alkoxy, C₁-C₆-alkyl, hydroxyC₁-C₆-alkyl,aminoC₁-C₆-alkyl, C₁-C₆-alkylamino, alkylsulfenyl, alkylsulfinyl,alkylsulfonyl, sulfamoyl, or trifluoromethyl. As in all examples hereinC₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). Examples of heteroarylgroups include, but are not limited to, unsubstituted and mono- ordi-substituted derivatives of furan, benzofuran, thiophene,benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole,isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole,imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline,isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan,1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole,benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole,quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. Insome embodiments, the substituents are halo, hydroxy, cyano,O—C₁-C₆-alkyl, C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, and amino-C₁-C₆-alkyl.

As used herein, the term “non-aromatic ring” refers to a groupcontaining a covalently closed ring that does not have a delocalizedπ-electron system.

As used herein, the term “cycloalkyl” refers to a group containing anon-aromatic ring wherein each of the atoms forming the ring is a carbonatom. Cycloalkyl rings can be formed by three, four, five, six, seven,eight, nine, or more than nine carbon atoms. Cycloalkyls can beoptionally substituted. In certain embodiments, a cycloalkyl containsone or more unsaturated bonds. Examples of cycloalkyls include, but arenot limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene,cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene,1,4-cyclohexadiene, cycloheptane, and cycloheptene.

As used herein, the term “non-aromatic heterocycle” refers to a groupcontaining a non-aromatic ring wherein one or more atoms forming thering is a heteroatom. Non-aromatic heterocyclic rings can be formed bythree, four, five, six, seven, eight, nine, or more than nine atoms.Non-aromatic heterocycles can be optionally substituted. In certainembodiments, non-aromatic heterocycles contain one or more carbonyl orthiocarbonyl groups such as, for example, oxo- and thio-containinggroups. Examples of non-aromatic heterocycles include, but are notlimited to, lactams, lactones, cyclic imides, cyclic thioimides, cycliccarbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine,1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine,1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine,2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituricacid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane,hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane,1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, and1,3-oxathiolane.

As used herein, the term “arylalkyl” refers to a group containing anaryl group bound to an alkyl group.

As used herein, the term “carbocycloalkyl” refers to a group containinga carbocyclic cycloalkyl ring. Carbocycloalkyl rings can be formed bythree, four, five, six, seven, eight, nine, or more than nine carbonatoms. Carbocycloalkyl groups can be optionally substituted.

As used herein, the term “ring” refers to any covalently closedstructure. Rings include, for example, carbocycles (e.g., aryls andcycloalkyls), heterocycles (e.g., heteroaryls and non-aromaticheterocycles), aromatics (e.g., aryls and heteroaryls), andnon-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Ringscan be optionally substituted. Rings can form part of a ring system.

As used herein, the term “ring system” refers to two or more rings,wherein two or more of the rings are fused. The term “fused” refers tostructures in which two or more rings share one or more bonds.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from alkyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andnon-aromatic heterocycle (bonded through a ring carbon).

As used herein, the term “O-carboxy” refers to a group of formulaRC(═O)O—.

As used herein, the term “C-carboxy” refers to a group of formula—C(═O)OR.

As used herein, the term “acetyl” refers to a group of formula—C(═O)CH₃.

As used herein, the term “trihalomethanesulfonyl” refers to a group offormula X₃CS(═O)₂— where X is a halogen.

As used herein, the term “cyano” refers to a group of formula —CN.

As used herein, the term “isocyanato” refers to a group of formula —NCO.

As used herein, the term “thiocyanato” refers to a group of formula—CNS.

As used herein, the term “isothiocyanato” refers to a group of formula—NCS.

As used herein, the term “sulfinyl” refers to a group of formula—S(═O)—R.

As used herein, the term “S-sulfonamido” refers to a group of formula—S(═O)₂NR₂.

As used herein, the term “N-sulfonamido” refers to a group of formulaRS(═O)₂NH—.

As used herein, the term “trihalomethanesulfonamido” refers to a groupof formula X₃CS(═O)₂NR—.

As used herein, the term “O-carbamyl” refers to a group of formula—OC(═O)—NR₂.

As used herein, the term “N-carbamyl” refers to a group of formulaROC(═O)NH—.

As used herein, the term “O-thiocarbamyl” refers to a group of formula—OC(═S)—NR₂.

As used herein, the term “N-thiocarbamyl” refers to a group of formulaROC(═S)NH—.

As used herein, the term “C-amido” refers to a group of formula—C(═O)—NR₂.

As used herein, the term “N-amido” refers to a group of formulaRC(═O)NH—.

As used herein, the term “ester” refers to a chemical moiety with theformula —(R)_(n)—COOR′, where R and R′ are independently selected fromalkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andnon-aromatic heterocycle (bonded through a ring carbon), where n is 0 or1.

As used herein, the term “amide” refers to a chemical moiety withformula —(R)_(n)—C(O)NHR′ or —(R)_(n)—NHC(O)R′, where R and R′ areindependently selected from alkyl, cycloalkyl, aryl, heteroaryl (bondedthrough a ring carbon) and heteroalicyclic (bonded through a ringcarbon), where n is 0 or 1. In certain embodiments, an amide can be anamino acid or a peptide.

As used herein, the terms “amine,” “hydroxy,” and “carboxyl” includesuch groups that have been esterified or amidified. Procedures andspecific groups used to achieve esterification and amidification areknown to those of skill in the art and can readily be found in referencesources such as Greene and Wuts, Protective Groups in Organic Synthesis,3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999, which isincorporated herein in its entirety.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

Unless otherwise indicated, the term “optionally substituted,” refers toa group in which none, one, or more than one of the hydrogen atoms hasbeen replaced with one or more group(s) individually and independentlyselected from: cycloalkyl, aryl, heteroaryl, non-aromatic heterocycle,hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,silyl, trihalomethanesulfonyl, and amino, including mono anddi-substituted amino groups, and the protected derivatives of aminogroups. Such protective derivatives (and protecting groups that can formsuch protective derivatives) are known to those of skill in the art andcan be found in references such as Greene and Wuts, above. Inembodiments in which two or more hydrogen atoms have been substituted,the substituent groups can together form a ring.

As used herein, the term “carrier” refers to a compound that facilitatesthe incorporation of another compound into cells or tissues. Forexample, dimethyl sulfoxide (DMSO) is a commonly used carrier forimproving incorporation of certain organic compounds into cells ortissues.

As used herein, the term “pharmaceutical agent” refers to a chemicalcompound or composition capable of inducing a desired therapeutic effectin a patient. In certain embodiments, a pharmaceutical agent contains anactive agent, which is the agent that induces the desired therapeuticeffect. In certain embodiments, a pharmaceutical agent is a prodrug. Incertain embodiments, a pharmaceutical agent contains inactiveingredients such as carriers, excipients, and the like.

As used herein, the term “therapeutically effective amount” refers to anamount of a pharmaceutical agent sufficient to achieve a desiredtherapeutic effect.

As used herein, a “prodrug” refers to an pharmaceutical agent that isconverted from a less active form into a corresponding more active formin vivo. A prodrug is a compound that, upon in vivo administration, ismetabolized by one or more steps or processes or otherwise converted tothe biologically, pharmaceutically or therapeutically active form of thecompound. To produce a prodrug, the pharmaceutically active compound ismodified such that the active compound will be regenerated by metabolicprocesses. The prodrug can be designed to alter the metabolic stabilityor the transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacodynamic processes and drug metabolism in vivo, those of skill inthis art, once a pharmaceutically active compound is known, can designprodrugs of the compound (see, e.g., Nogrady (1985) Medicinal ChemistryA Biochemical Approach, Oxford University Press, New York, pages388-392).

As used herein, the term “pharmaceutically acceptable” refers to aformulation of a compound that does not significantly abrogate thebiological activity, a pharmacological activity and/or other propertiesof the compound when the formulated compound is administered to apatient. In certain embodiments, a pharmaceutically acceptableformulation does not cause significant irritation to a patient.

As used herein, pharmaceutically acceptable derivatives of a compoundinclude salts, esters, enol ethers, enol esters, acetals, ketals,orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydratesor prodrugs thereof. Such derivatives can be readily prepared by thoseof skill in this art using known methods for such derivatization. Thecompounds produced can be administered to animals or humans withoutsubstantial toxic effects and either are pharmaceutically active or areprodrugs. Pharmaceutically acceptable salts include, but are not limitedto, amine salts, such as but not limited toN,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia,diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates. Pharmaceuticallyacceptable esters include, but are not limited to, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl andheterocyclyl esters of acidic groups, including, but not limited to,carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids,sulfinic acids and boronic acids. Pharmaceutically acceptable enolethers include, but are not limited to, derivatives of formula C═C(OR)where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkyl ar heterocyclyl. Pharmaceutically acceptableenol esters include, but are not limited to, derivatives of formulaC═C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl ar heterocyclyl.Pharmaceutically acceptable solvates and hydrates are complexes of acompound with one or more solvent or water molecules, or 1 to about 100,or 1 to about 10, or one to about 2, 3 or 4 solvent or water molecules.

It is to be understood that the compounds provided herein can containchiral centers. Such chiral centers can be of either the (R) or (S)configuration, or can be a mixture thereof. Thus, the compounds providedherein can be enantiomerically pure, or be stereoisomeric ordiastereomeric mixtures.

As used herein, substantially pure means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis, high performance liquid chromatography (HPLC) and massspectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notdetectably alter the physical and chemical properties, such as enzymaticand biological activities, of the substance. Thus, substantially pureobject species (e.g., compound) is the predominant species present(i.e., on a molar basis it is more abundant than any other individualspecies in the composition). In certain embodiments, a substantiallypurified fraction is a composition wherein the object species containsat least about 50 percent (on a molar basis) of all species present. Incertain embodiments, a substantially pure composition will contain morethan about 50%, 60%, 70%, 80%, 85%, 90%, 95%, or 99% of all speciespresent in the composition. In certain embodiments, a substantially purecomposition will contain more than about 80%, 85%, 90%, 95%, or 99% ofall species present in the composition. Methods for purification of thecompounds to produce substantially chemically pure compounds are knownto those of skill in the art. A substantially chemically pure compoundcan, however, be a mixture of stereoisomers. In such instances, furtherpurification might increase the specific activity of the compound. Theinstant disclosure is meant to include all such possible isomers, aswell as, their racemic and optically pure forms. Optically active (+)and (−), (R)- and (S)-, or (D)- and (L)-isomers can be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques, such as reverse phase HPLC. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

As used herein, the term “co-administer” refers to administering morethan one pharmaceutical agent to a patient. In certain embodiments,co-administered pharmaceutical agents are administered together in asingle dosage unit. In certain embodiments, co-administeredpharmaceutical agents are administered separately. In certainembodiments, co-administered pharmaceutical agents are administered atthe same time. In certain embodiments, co-administered pharmaceuticalagents are administered at different times.

As used herein “subject” is an animal, typically a mammal, includinghuman.

As used herein, the term “patient” includes human and animal subjects.

As used herein, the term “tissue-selective” refers to the ability of acompound to modulate a biological activity in one tissue to a greater orlesser degree than it modulates a biological activity in another tissue.The biological activities in the different tissues can be the same orthey can be different. The biological activities in the differenttissues can be mediated by the same type of target receptor. Forexample, in certain embodiments, a tissue-selective compound canmodulate an androgen receptor mediated biological activity in one tissueand fail to modulate, or modulate to a lesser degree, an androgenreceptor mediated biological activity in another tissue type.

As used herein, the term “monitoring” refers to observing an effect orabsence of any effect. In certain embodiments, one monitors cells aftercontacting those cells with a compound provided herein. Examples ofeffects that can be monitored include, but are not limited to, changesin cell phenotype, cell proliferation, androgen receptor activity, orthe interaction between an androgen receptor and a natural bindingpartner.

As used herein, the term “cell phenotype” refers to physical orbiological characteristics. Examples of characteristics that constitutephenotype included, but are not limited to, cell size, cellproliferation, cell differentiation, cell survival, apoptosis (celldeath), or the utilization of a metabolic nutrient (e.g., glucoseuptake). Certain changes or the absence of changes in cell phenotype arereadily monitored using techniques known in the art.

As used herein, the term “cell proliferation” refers to the rate atwhich cells divide. The number of cells growing in a vessel can bequantified by a person skilled in the art (e.g., by counting cells in adefined area using a light microscope, or by using laboratory apparatusthat measure the density of cells in an appropriate medium). One skilledin that art can calculate cell proliferation by determining the numberof cells at two or more times.

As used herein, the term “contacting” refers to bringing two or morematerials into close enough proximity that they can interact. In certainembodiments, contacting can be accomplished in a vessel such as a testtube, a petri dish, or the like. In certain embodiments, contacting canbe performed in the presence of additional materials. In certainembodiments, contacting can be performed in the presence of cells. Incertain of such embodiments, one or more of the materials that are beingcontacted can be inside a cell. Cells can be alive or can be dead. Cellscan or cannot be intact.

B. Compounds

Certain compounds that bind to androgen receptors and/or modulate anactivity of such receptors play a role in health (e.g., normal growth,development, and/or absence of disease). In certain embodiments,selective androgen receptor modulators and/or binding compounds areuseful for treating any of a variety of diseases or conditions.

Certain compounds have been previously described as receptor modulatorsor as possible receptor modulators. See e.g., U.S. Pat. Nos. 6,462,038,5,693,646; 6,380,207; 6,506,766; 5,688,810; 5,696,133; 6,569,896,6,673,799; 4,636,505; 4,097,578; 3,847,988; U.S. application Ser. No.10/209,461 (Pub. No. US 2003/0055094); WO 01/27086; WO 02/22585; Zhi,et. al. Bioorganic & Medicinal Chemistry Letters 2000, 10, 415-418;Pooley, et. al., J. Med. Chem. 1998, 41, 3461; Hamann, et al. J. Med.Chem. 1998, 41(4), 623; and Yin, et al., Molecular Pharmacology, 2003,63 (1), 211-223 the entire disclosures of which are incorporated intheir entirety.

In certain embodiments, the compounds provided herein are selectiveandrogen receptor modulators. In certain embodiments, the compoundsprovided herein are selective androgen receptor binding agents. Incertain embodiments, provided herein are methods of making and methodsof using androgen receptor modulators and/or androgen binding agentsprovided herein. In certain embodiments, selective androgen modulatorsare agonists, partial agonists, and/or antagonists for the androgenreceptor.

In certain embodiments, the compounds provided herein have a structureselected from Formula I, Formula II, Formula III, Formula IV, Formula V,and Formula VI:

wherein:

R¹ and R² are each independently selected from hydrogen, F, Cl, Br, I,OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, COR^(A), CO₂R^(A), CONR^(A)R^(B), SOR^(A), SO₂R^(A), andSO₂NR^(A)R^(B), NHCOR^(A), and NHCONR^(A)R^(B), provided that at leastone of R¹ and R² is not hydrogen;

R³, R^(3a), R⁴, and R⁵ are each independently selected from hydrogen, F,Cl, OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl;

wherein if R¹ is NO₂ and R^(3a) is F, then at least one of R² and R⁴ andR⁵ is not hydrogen; and wherein if R¹ is NO₂ and R³ is F, then Z is notO;

R⁶, R⁷, R¹⁰, and R¹¹ are each independently selected from hydrogen, anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionallysubstituted C₂-C₆ alkynyl, and an optionally substituted C₂-C₆ alkenyl;

R^(6a) and R^(7a) are each independently selected from hydrogen, anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionallysubstituted C₂-C₆ alkynyl, and an optionally substituted C₂-C₆ alkenyl;or R^(6a) and R^(7a) together form a carbonyl;

R⁸ and R⁹ are each independently selected from hydrogen, an optionallysubstituted C₁-C₈ alkyl, an optionally substituted C₂-C₈ alkenyl, anoptionally substituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, C₁-C₈ heteroalkyl, an optionally substituted C₂-C₈heteroalkenyl, an optionally substituted C₂-C₈ alkynyl, an optionallysubstituted C₂-C₈ haloalkynyl, an optionally substituted C₂-C₈heteroalkynyl, an optionally substituted aryl, an optionally substitutedheteroaryl, CH(R^(D))OR^(A), CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C);

R¹² and R¹³ are each independently selected from hydrogen, F, Cl,OR^(A), NR^(A)R^(B), SR^(A), an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆heteroalkyl, an optionally substituted C₂-C₆ alkynyl, an optionallysubstituted C₂-C₆ alkenyl, and (CH₂)_(m)R^(C);

R¹⁴ and R¹⁵ are each independently selected from hydrogen, F, Cl, Br, I,OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B), COR^(A), CO₂R^(A),CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B);

R¹⁶ and R¹⁷ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl;

R¹⁸ and R¹⁹ are each independently selected from hydrogen, F, Cl, Br, I,OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B), COR^(A), CO₂R^(A),CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B);

R²⁰ and R²¹ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl; wherein if R¹⁸ is NO₂ and X is O, then atleast one of R¹⁹, R²⁰, and R²¹ is not hydrogen, and wherein if R¹⁹ isNO₂ and X is C, then at least one of R¹⁸, R²⁰, and R²¹ is not hydrogen;

R²² is selected from hydrogen, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, COR⁶, CO₂R^(A), CONR^(A)R^(B), SO₂R^(A), an optionallysubstituted aryl, an optionally substituted heteroaryl,CH₂CH(R^(D))OR^(A), CH₂CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C), whereinthe optionally substituted aryl or optionally substituted heteroaryl isoptionally substituted with a substituent selected from F, Cl, Br, I,CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A), SO₂R^(A), an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, andan optionally substituted C₁-C₄ heteroalkyl;

R²³ and R²⁴ are each independently selected from hydrogen, an optionallysubstituted C₁-C₈ alkyl, an optionally substituted C₂-C₈ alkenyl, anoptionally substituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, an optionally substituted C₁-C₈ heteroalkyl, an optionallysubstituted C₂-C₈ heteroalkenyl, an optionally substituted C₂-C₈alkynyl, an optionally substituted C₂-C₈ haloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C); or R²³ and R²⁴ together form acarbonyl group, provided that if R¹⁸ is NO₂ and X is NH, then R²³ andR²⁴ do not together form a carbonyl group; or

R²² and R²³ are optionally linked to form a ring; or

R²³ and R²⁵ are optionally linked to form a ring;

X is selected from O, S, CR^(A)R^(B), NR^(D), and a bond;

wherein if X is CR^(A)R^(B) or a bond, then R²⁵ and R²⁶ are eachindependently selected from a halogen, OR^(A), NR^(A)R^(B), hydrogen, anoptionally substituted C₁-C₈ alkyl, an optionally substituted C₂-C₈alkenyl, an optionally substituted C₁-C₈ haloalkyl, an optionallysubstituted C₂-C₈ haloalkenyl, an optionally substituted C₁-C₈heteroalkyl, an optionally substituted C₂-C₈ heteroalkenyl, anoptionally substituted C₂-C₈ alkynyl, an optionally substituted C₂-C₈haloalkynyl, an optionally substituted C₂-C₈ heteroalkynyl, anoptionally substituted aryl, an optionally substituted heteroaryl, and(CH₂)_(m)R^(C); or R²⁵ and R²⁶ together form a carbonyl group;

and wherein if X is O, S, or NR^(D), then R²⁵ and R²⁶ are eachindependently selected from hydrogen, an optionally substituted C₁-C₈alkyl, an optionally substituted C₂-C₈ alkenyl, an optionallysubstituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, an optionally substituted C₁-C₈ heteroalkyl, an optionallysubstituted C₂-C₈ heteroalkenyl, an optionally substituted C₂-C₈alkynyl, an optionally substituted C₂-C₈ haloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, and (CH₂)_(m)R^(C); or R²⁵ and R²⁶together form a carbonyl group;

R^(A) and R^(B) are each independently selected from hydrogen, anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, and an optionally substituted C₁-C₄ heteroalkyl;

R^(C) is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl that is optionally with a substituent selectedfrom F, Cl, Br, I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(a), SOR^(A),SO₂R^(A), an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl;

R^(D) is selected from hydrogen, an optionally substituted C₁-C₄ alkyl,an optionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl;

Z is selected from O, S, CR^(A)R^(B), and NR^(D);

n is 0, 1, or 2; and

m is 1 or 2.

In certain embodiments, R¹ and R² are each independently selected fromhydrogen, F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, anoptionally substituted C₁-C₄ heteroalkyl, COR^(A), CO₂R^(A),CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B), NHCOR^(A),NHCONR^(A)R^(B). In certain embodiments, R¹ and R² are not bothhydrogen.

In certain embodiments, R³, R^(3a), R⁴, and R⁵ are each independentlyselected from hydrogen, F, Cl, OR^(A), an optionally substituted C₁-C₄alkyl, and an optionally substituted C₁-C₄ haloalkyl. In certainembodiments, if R¹ is NO₂ and R^(3a) is F, then at least one of R² andR⁴ and R⁵ is not hydrogen. In certain embodiments, if R¹ is NO₂ and R³is F, then Z is not O.

In certain embodiments, R⁶, R⁷, R¹⁰, and R¹¹ are each independentlyselected from hydrogen, an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆heteroalkyl, an optionally substituted C₂-C₆ alkynyl, and an optionallysubstituted C₂-C₆ alkenyl. In certain embodiments, R^(6a) and R^(7a) areeach independently selected from hydrogen, an optionally substitutedC₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, an optionallysubstituted C₁-C₆ heteroalkyl, an optionally substituted C₂-C₆ alkynyl,and an optionally substituted C₂-C₆ alkenyl. In certain embodiments,R^(6a) and R^(7a) together form a carbonyl.

In certain embodiments, R⁸ and R⁹ are each independently selected fromhydrogen, an optionally substituted C₁-C₈ alkyl, an optionallysubstituted C₂-C₈ alkenyl, an optionally substituted C₁-C₈ haloalkyl, anoptionally substituted C₂-C₈ haloalkenyl, C₁-C₈ heteroalkyl, anoptionally substituted C₂-C₈ heteroalkenyl, an optionally substitutedC₂-C₈ alkynyl, an optionally substituted C₂-C₈ haloalkynyl, anoptionally substituted C₂-C₈ heteroalkynyl, an optionally substitutedaryl, an optionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C). In certain embodiments, R¹²and R¹³ are each independently selected from hydrogen, F, Cl, OR^(A),NR^(A)R^(B), SR^(A), an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆heteroalkyl, an optionally substituted C₂-C₆ alkynyl, an optionallysubstituted C₂-C₆ alkenyl, and (CH₂)_(m)R^(C).

In certain embodiments, R¹⁴ and R¹⁵ are each independently selected fromhydrogen, F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, anoptionally substituted C₁-C₄ heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B),COR^(A), CO₂R^(A), CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B).

In certain embodiments, R¹⁶ and R¹⁷ are each independently selected fromhydrogen, F, Cl, OR^(A), an optionally substituted C₁-C₄ alkyl, and anoptionally substituted C₁-C₄ haloalkyl.

In certain embodiments, R¹⁸ and R¹⁹ are each independently selected fromhydrogen, F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, anoptionally substituted C₁-C₄ heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B),COR^(A), CO₂R^(A), CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B).

In certain embodiments, R²⁰ and R²¹ are each independently selected fromhydrogen, F, Cl, OR^(A), an optionally substituted C₁-C₄ alkyl, and anoptionally substituted C₁-C₄ haloalkyl.

In certain embodiments, R²² is selected from hydrogen, an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, anoptionally substituted C₁-C₄ heteroalkyl, COR^(A), CO₂R^(A),CONR^(A)R^(B), SO₂R^(A), an optionally substituted aryl, an optionallysubstituted heteroaryl, CH₂CH(R^(D))OR^(A), CH₂CH(R^(D))NR^(A)R^(B), and(CH₂)_(m)R^(C). In certain of such embodiments, the optionallysubstituted aryl or optionally substituted heteroaryl is optionallysubstituted with a substituent selected from F, Cl, Br, I, CN, OR^(A),NO₂, NR^(A)R^(B), SR^(A), SOR^(A), SO₂R^(A), an optionally substitutedC₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, and anoptionally substituted C₁-C₄ heteroalkyl.

In certain embodiments, R²³ and R²⁴ are each independently selected fromhydrogen, an optionally substituted C₁-C₈ alkyl, an optionallysubstituted C₂-C₈ alkenyl, an optionally substituted C₁-C₈ haloalkyl, anoptionally substituted C₂-C₈ haloalkenyl, an optionally substitutedC₁-C₈ heteroalkyl, an optionally substituted C₂-C₈ heteroalkenyl, anoptionally substituted C₂-C₈ alkynyl, an optionally substituted C₂-C₈haloalkynyl, an optionally substituted C₂-C₈ heteroalkynyl, anoptionally substituted aryl, an optionally substituted heteroaryl,CH(R^(D))OR^(A), CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C). In certainembodiments, R²³ and R²⁴ together form a carbonyl group.

In certain embodiments, R²² and R²³ are optionally linked to form aring.

In certain embodiments, R²³ and R²⁵ are optionally linked to form aring.

In certain embodiments, X is selected from O, S, CR^(A)R^(A), NR^(D),and a bond.

In certain embodiments, if X is CR^(A)R^(B) or a bond, then R²⁵ and R²⁶are each independently selected from a halogen, OR^(A), NR^(A)R^(B),hydrogen, an optionally substituted C₁-C₈ alkyl, an optionallysubstituted C₂-C₈ alkenyl, an optionally substituted C₁-C₈ haloalkyl, anoptionally substituted C₂-C₈ haloalkenyl, an optionally substitutedC₁-C₈ heteroalkyl, an optionally substituted C₂-C₈ heteroalkenyl, anoptionally substituted C₂-C₈ alkynyl, an optionally substituted C₂-C₈haloalkynyl, an optionally substituted C₂-C₈ heteroalkynyl, anoptionally substituted aryl, an optionally substituted heteroaryl, and(CH₂)_(m)R^(C). In certain embodiments, R²⁵ and R²⁶ together form acarbonyl group.

In certain embodiments, if X is O, S, or NR^(D), then R²⁵ and R²⁶ areeach independently selected from hydrogen, an optionally substitutedC₁-C₈ alkyl, an optionally substituted C₂-C₈ alkenyl, an optionallysubstituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, an optionally substituted C₁-C₈ heteroalkyl, an optionallysubstituted C₂-C₈ heteroalkenyl, an optionally substituted C₂-C₈alkynyl, an optionally substituted C₂-C₈ haloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, and (CH₂)_(m)R^(C). In certainembodiments R²⁵ and R²⁶ together form a carbonyl group.

In certain embodiments, R^(A) and R^(B) are each independently selectedfrom hydrogen, an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl.

In certain embodiments, R^(C) is selected from an optionally substitutedaryl and an optionally substituted heteroaryl that is optionally with asubstituent selected from F, Cl, Br, I, CN, OR^(A), NO₂, NR^(A)R^(B),SR^(A), SOR^(A), SO₂R^(A), an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl.

In certain embodiments, R^(D) is selected from hydrogen, an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, andan optionally substituted C₁-C₄ heteroalkyl.

In certain embodiments, Z is selected from O, S, CR^(A)R^(B), andNR^(D). In certain embodiments, n is 0, 1, or 2. In certain embodiments,m is 1 or 2. In certain embodiments, if R¹⁸ is NO₂ and X is O, then R¹⁹,R²⁰, and R²¹ are not each hydrogen. In certain embodiments, if R¹⁹ isNO₂ and X is C, then at least one of R¹⁸, R²⁰, and R²¹ is not hydrogen.In certain embodiments, if R¹⁸ is NO₂ and X is NH, then R²³ and R²⁴ donot together form a carbonyl.

Compounds of Formula II and Formula IV

In certain embodiments, the compounds provided herein have Formula II orFormula IV:

wherein the variables are as described elsewhere herein.

In another embodiment, the compounds have Formula II or Formula IV,wherein R¹ and R₂ are each independently selected from hydrogen, F, Cl,Br, I, OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl,an optionally substituted C₁-C₄ haloalkyl, an optionally substitutedC₁-C₄ heteroalkyl, COR^(A), CO₂R^(A), CONR^(A)R^(B), SOR^(A), SO₂R^(A),and SO₂NR^(A)R^(B), NHCOR^(A), and NHCONR^(A)R^(B), provided that atleast one of R¹ and R² is not hydrogen;

R³, R⁴, and R⁵ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl;

wherein if R¹ is NO₂ and R³ is F, then Z is not O;

R⁶, R⁷, and R¹⁰ are each independently selected from hydrogen, anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl, an optionally substituted C₁-C₆heterohaloalkenyl, an optionally substituted C₁-C₆ heterohaloalkynyl, anoptionally substituted C₂-C₆ alkynyl, and an optionally substitutedC₂-C₆ alkenyl;

R^(6a) and R^(7a) are each independently selected from hydrogen, anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl, an optionally substituted C₂-C₆heterohaloalkenyl, an optionally substituted C₂-C₆ heterohaloalkynyl, anoptionally substituted C₂-C₆ alkynyl, and an optionally substitutedC₂-C₆ alkenyl; or R^(6a) and R^(7a) together form a carbonyl;

R⁹ is selected from hydrogen, an optionally substituted C₁-C₈ alkyl, anoptionally substituted C₂-C₈ alkenyl, an optionally substituted C₁-C₈haloalkyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ heterohaloalkenyl, an optionallysubstituted C₂-C₆ heterohaloalkynyl, an optionally substituted C₂-C₈haloalkenyl, C₁-C₈ heteroalkyl, an optionally substituted C₂-C₈heteroalkenyl, an optionally substituted C₂-C₈ alkynyl, an optionallysubstituted C₂-C₈ haloalkynyl, an optionally substituted C₂-C₈heteroalkynyl, an optionally substituted aryl, an optionally substitutedheteroaryl, CH(R^(D))OR^(A), CH(R^(D))NR^(A)R^(B), COR^(A), CO₂R^(A) and(CH₂)_(m)R^(C);

R¹² and R¹³ are each independently selected from hydrogen, F, Cl,OR^(A), NR^(A)R^(B), SR^(A), an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆heteroalkyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ heterohaloalkenyl, an optionallysubstituted C₂-C₆ heterohaloalkynyl, an optionally substituted C₂-C₆alkynyl, an optionally substituted C₂-C₆ alkenyl, and (CH₂)_(m)R^(C);

R¹⁴ and R¹⁵ are each independently selected from hydrogen, F, Cl, Br, I,OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B), COR^(A), CO₂R^(A),CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B);

R¹⁶ and R¹⁷ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl;

R^(A) and R^(B) are each independently selected from hydrogen, anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, and an optionally substituted C₁-C₄ heteroalkyl;

R^(C) is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl that is optionally with a substituent selectedfrom F, Cl, Br, I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A),SO₂R^(A), an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl;

R^(D) is selected from hydrogen, an optionally substituted C₁-C₄ alkyl,an optionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl;

Z is selected from O, S, CR^(A)R^(B), and NR^(D);

n is 0, 1, or 2; and

m is 1 or 2.

In certain embodiments, R¹ is selected from NO₂ and CN. In certainembodiments, R² is hydrogen, optionally substituted C₁-C₄ alkyl or anoptionally substituted C₁-C₄ haloalkyl. In certain embodiments, R² is anoptionally substituted C₁-C₄ alkyl or an optionally substituted C₁-C₄haloalkyl. In certain embodiments, R² is hydrogen or trifluoromethyl. Incertain embodiments, R² is trifluoromethyl.

In certain embodiments, R³, R⁴, and R⁵ are each independently selectedfrom hydrogen, F, Cl, and an optionally substituted C₁-C₄ alkyl. Incertain embodiments, R³, R⁴, and R⁵ are each independently selected fromF, Cl, and an optionally substituted C₁-C₄ alkyl. In certainembodiments, R³ is hydrogen. In certain embodiments, R⁴ is hydrogen. Incertain embodiments, R⁵ is hydrogen.

In certain embodiments, R^(6a) and R^(7a) are each independentlyselected from hydrogen, an optionally substituted C₁-C₆ alkyl; anoptionally substituted C₁-C₆ heterohaloalkyl; an optionally substitutedC₂-C₆ heterohaloalkenyl and an optionally substituted C₂-C₆heterohaloalkynyl, or R^(6a) and R^(7a) together form a carbonyl. Incertain embodiments, R^(6a) and R^(7a) are each independently selectedfrom an optionally substituted C₁-C₆ alkyl; an optionally substitutedC₁-C₆ heterohaloalkyl; an optionally substituted C₂-C₆ heterohaloalkenyland an optionally substituted C₂-C₆ heterohaloalkynyl, or R^(6a) andR^(7a) together form a carbonyl. In certain embodiments, R^(6a) ishydrogen. In certain embodiments, R^(7a) is hydrogen or an optionallysubstituted C₁-C₆ alkyl. In certain embodiments, R^(7a) is an optionallysubstituted C₁-C₆ alkyl. In certain embodiments, R^(7a) is hydrogen ormethyl. In certain embodiments, R^(7a) is hydrogen. In certainembodiments, R^(7a) is methyl. In certain embodiments, R^(6a) and R^(7a)together form a carbonyl.

In certain embodiments, R¹⁰ is selected from hydrogen, an optionallysubstituted C₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, anoptionally substituted C₁-C₆ heteroalkyl, an optionally substitutedC₂-C₆ heterohaloalkenyl, an optionally substituted C₂-C₆heterohaloalkynyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ alkynyl, and an optionally substitutedC₂-C₆ alkenyl. In certain embodiments, R¹⁰ is selected from anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionallysubstituted C₂-C₆ heterohaloalkenyl, an optionally substituted C₂-C₆heterohaloalkynyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ alkynyl, and an optionally substitutedC₂-C₆ alkenyl. In certain embodiments, R¹⁰ is hydrogen.

In certain embodiments, R⁹ is selected from hydrogen, F, Cl, Br, I, anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₆heterohaloalkyl, an optionally substituted C₂-C₆ heterohaloalkenyl, anoptionally substituted C₂-C₆ heterohaloalkynyl, COR^(A), CO₂R^(A),CH(R^(D))OR^(A) and CH(R^(D))NR^(A)R^(B). In certain embodiments, R⁹ isselected from F, Cl, Br, I, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₆ heterohaloalkyl, an optionally substitutedC₂-C₆ heterohaloalkenyl, an optionally substituted C₂-C₆heterohaloalkynyl, COR^(A), CO₂R^(A), CH(R^(D))OR^(A) andCH(R^(D))NR^(A)R^(B).

In certain embodiments, R⁹ is hydrogen, formyl, hydroxy C₁-C₆alkyl,hydroxyhaloC₁-C₆alkyl, C₁-C₆alkylsilyloxy C₁-C₆alkyl,C₁-C₆alkoxycarbonyl, aminoC₁-C₆alkyl, carboxy, orC₁-C₆alkylcarbonyloxyC₁-C₆alkyl. In certain embodiments, R⁹ is formyl,hydroxy C₁-C₆alkyl, hydroxyhaloC₁-C₆alkyl, C₁-C₆alkylsilyloxyC₁-C₆alkyl, C₁-C₆alkoxycarbonyl, aminoC₁-C₆alkyl, carboxy, orC₁-C₆alkylcarbonyloxyC₁-C₆alkyl.

In other embodiments, R⁹ is hydrogen, formyl, hydroxymethyl,1-hydroxy-2,2,2-trifluoroethyl, tributylsilyloxymethyl, ethoxycarbonyl,aminomethyl, carboxy, or acetyoxymethyl. In other embodiments, R⁹ isformyl, hydroxymethyl, 1-hydroxy-2,2,2-trifluoroethyl,tributylsilyloxymethyl, ethoxycarbonyl, aminomethyl, carboxy, oracetyoxymethyl.

In certain embodiments, R¹² and R¹³ are each independently selected fromhydrogen, F, Cl, OR^(A), an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₁-C₆ heterohaloalkyl, an optionally substitutedC₂-C₆ heterohaloalkenyl, an optionally substituted C₂-C₆heterohaloalkynyl, and (CH₂)_(m)R^(C). In certain embodiments, R¹² andR¹³ are each independently selected from F, Cl, OR^(A), an optionallysubstituted C₁-C₆ alkyl, an optionally substituted C₁-C₆heterohaloalkyl, an optionally substituted C₂-C₆ heterohaloalkenyl, anoptionally substituted C₂-C₆ heterohaloalkynyl, and (CH₂)_(m)R^(C). Incertain embodiments, R¹² is hydrogen. In certain embodiments, R¹³ ishydrogen, F, OH or benzyl. In certain embodiments, R¹³ is F, OH orbenzyl.

In another embodiment, the compounds provided herein have Formula II orFormula IV, wherein at least one of R^(6a), R^(7a), R⁶, R⁷, R⁹, R¹⁰, R¹²and R¹³ is an optionally substituted C₁-C₆ heterohaloalkyl; and theother variables are as described elsewhere herein. In anotherembodiment, the compounds provided herein have Formula II, wherein atleast one of R^(6a), R^(7a), R⁹, R¹⁰, R¹² and R¹³ is an optionallysubstituted C₁-C₆ heterohaloalkyl; and the other variables are asdescribed elsewhere herein. In another embodiment, the compoundsprovided herein have Formula IV, wherein at least one of R⁶, R⁷, R⁹,R¹⁰, R¹² and R¹³ is an optionally substituted C₁-C₆ heterohaloalkyl; andthe other variables are as described elsewhere herein.

In certain embodiments, the compounds are of Formula II, wherein R¹ isselected from NO₂ and CN;

R² is hydrogen, optionally substituted C₁-C₄ alkyl or an optionallysubstituted C₁-C₄ haloalkyl;

R³, R⁴, and R⁵ are each independently selected from hydrogen, F, Cl, andan optionally substituted C₁-C₄ alkyl;

R^(6a) and R^(7a) are each independently selected from hydrogen and anoptionally substituted C₁-C₆ alkyl; an optionally substituted C₁-C₆heterohaloalkyl or R^(6a) and R^(7a) together form a carbonyl;

R⁹ is selected from hydrogen, F, Cl, Br, I, an optionally substitutedC₁-C₄ alkyl, an optionally substituted C₁-C₆ heterohaloalkyl, COR^(A),CO₂R^(A), CH(R^(D))OR^(A), and CH(R^(D))NR^(A)R^(B);

R¹⁰ is hydrogen;

R¹² and R¹³ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₁-C₆ heterohaloalkyl and (CH₂)_(m)R^(C); and other variables are asdescribed elsewhere herein.

In certain embodiments, the compounds are of Formula II, wherein R¹ isselected from NO₂ and CN;

R² is an optionally substituted C₁-C₄ alkyl or an optionally substitutedC₁-C₄ haloalkyl;

R³, R⁴, and R⁵ are each independently selected from F, Cl, and anoptionally substituted C₁-C₄ alkyl;

R^(6a) and R^(7a) are each independently selected from an optionallysubstituted C₁-C₆ alkyl; an optionally substituted C₁-C₆ heterohaloalkylor R^(6a) and R^(7a) together form a carbonyl;

R⁹ is selected from F, Cl, Br, I, an optionally substituted C₁-C₄ alkyl,an optionally substituted C₁-C₆ heterohaloalkyl, COR^(A), CO₂R^(A),CH(R^(D))OR^(A), and CH(R^(D))NR^(A)R^(B);

R¹⁰ is hydrogen;

R¹² and R¹³ are each independently selected from F, Cl, OR^(A), anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆heterohaloalkyl and (CH₂)_(m)R^(C); and other variables are as describedelsewhere herein.

In certain embodiments, the compounds have formula IIA,

wherein the variables are as described elsewhere herein.

In certain embodiments, the compounds have formula IIB,

wherein the variables are as described elsewhere herein. In certainembodiments, the compounds have formula IIB, wherein R¹ is selected fromNO₂ and CN;

R² is hydrogen, optionally substituted C₁-C₄ alkyl or an optionallysubstituted C₁-C₄ haloalkyl;

R³, R⁴, and R⁵ are each independently selected from hydrogen, F, Cl, andan optionally substituted C₁-C₄ alkyl;

R^(6a) and R^(7a) are each independently selected from hydrogen and anoptionally substituted C₁-C₆ alkyl; an optionally substituted C₁-C₆heterohaloalkyl, or R^(6a) and R^(7a) together form a carbonyl;

R⁹ is selected from hydrogen, F, Cl, Br, I, an optionally substitutedC₁-C₄ alkyl, an optionally substituted C₁-C₆ heterohaloalkyl, COR^(A),CO₂R^(A), CH(R^(D))OR^(A), and CH(R^(D))NR^(A)R^(B);

R¹⁰ is hydrogen; and

R¹² and R¹³ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₁-C₆ heterohaloalkyl and (CH₂)_(m)R^(C).

In certain embodiments, the compounds of formula IIB, wherein R¹ isselected from NO₂ and CN;

R² is hydrogen or an optionally substituted C₁-C₄ haloalkyl;

R³, R⁴, and R⁵ are each independently selected from hydrogen and anoptionally substituted C₁-C₄ alkyl;

R^(6a) and R^(7a) are each independently selected from hydrogen and anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆heterohaloalkyl; or R^(6a) and R^(7a) together form a carbonyl;

R⁹ is selected from hydrogen, an optionally substituted C₁-C₆heterohaloalkyl, F, Cl, COR^(A), CO₂R^(A), CH(R^(D))OR^(A), andCH(R^(D))NR^(A)R^(B);

R¹⁰ is hydrogen; and

R¹² and R¹³ are each independently selected from hydrogen, optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₆heterohaloalkyl, OR^(A), and (CH₂)_(m)R^(C).

In certain embodiments, in the compounds of formula IIB, R¹ is selectedfrom NO₂ and CN;

R² is hydrogen or trifluoromethyl;

R³, R⁴, are R⁵ each hydrogen;

R^(7a) is hydrogen or methyl and R^(6a) is hydrogen; or R^(6a) andR^(7a) together form a carbonyl;

R⁹ is selected from hydrogen, formyl, hydroxymethyl,1-hydroxy-2,2,2-trifluoroethyl, tributylsilyloxymethyl, ethoxycarbonyl,aminomethyl, carboxy, and acetyoxymethyl

R¹⁰ is hydrogen;

R¹² is hydrogen; and

R¹³ is selected from hydrogen, F, OH and benzyl.

In certain embodiments, the compounds have formula:

wherein the variables are as described elsewhere herein. In certainembodiments, at least one of R^(7a), R⁹ and R¹³ is an optionallysubstituted C₁-C₆ heterohaloalkyl. In certain embodiments, R^(7a) is anoptionally substituted C₁-C₆ heterohaloalkyl. In certain embodiments, R⁹is an optionally substituted C₁-C₆ heterohaloalkyl. In certainembodiments, R¹³ is an optionally substituted C₁-C₆ heterohaloalkyl.

In another embodiment, the compounds have formula:

wherein the variables are as described elsewhere herein.

In certain embodiments, the compounds have formula:

wherein the variables are as described elsewhere herein.

In certain embodiments, the compounds have formula:

wherein the variables are as described elsewhere herein.

In certain embodiments, the compounds have Formula IIC or IID:

wherein the variables are as described elsewhere herein.

In certain embodiments, the compounds have formula IID:

wherein the variables are as described elsewhere herein. In certainembodiments the compounds have formula IID, wherein R¹ is NO₂; R₂ ishydrogen or haloalkyl; R³, R⁴, R⁵, R^(6a), R^(7a), R⁹, R¹², and R¹³ areeach hydrogen; and R⁹ is selected from CO₂R^(A) CH(R^(D))OR^(A), andCH(R^(D))NR^(A)R^(B). In certain embodiments the compounds have formulaIID, wherein R¹ is NO₂; R₂ is hydrogen or trifluoromethyl; R³, R⁴, R⁵,R^(6a), R^(7a), R⁹, R¹², and R¹³ are each hydrogen; and R⁹ is selectedfrom hydroxymethyl, ethoxycarbonyl and acetyoxymethyl.

In certain embodiments, the compounds have formula:

wherein the variables are as described elsewhere herein.

In certain embodiments, the compounds have formula:

wherein the variables are as described elsewhere herein.

In certain embodiments, the compounds have Formula:

wherein the variables are as described elsewhere herein.

In other embodiments, the compounds have formula:

wherein the variables are as described elsewhere herein.

Compounds of Formula V or VI

In other embodiments, the compounds have formula:

wherein the variables are as described elsewhere herein.

In certain embodiments, the compounds have Formula (V) or VI, whereinR¹⁸ and R¹⁹ are each independently selected from hydrogen, F, Cl, Br, I,OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B), COR^(A), CO₂R^(A),CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B);

R²⁰ and R²¹ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl; wherein if R¹⁸ is NO₂ and X is O, then atleast one of R¹⁹, R²⁰, and R²¹ is not hydrogen, and wherein if R¹⁹ isNO₂ and X is C, then at least one of R¹⁸, R²⁰, and R²¹ is not hydrogen;

R²² is selected from hydrogen, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ heterohaloalkenyl, an optionallysubstituted C₂-C₆ heterohaloalkynyl, COR⁶, CO₂R^(A), CONR^(A)R^(B),SO₂R^(A), an optionally substituted aryl, an optionally substitutedheteroaryl, CH₂CH(R^(D))OR^(A), CH₂CH(R^(D))NR^(A)R^(B), and(CH₂)_(m)R^(C), wherein the optionally substituted aryl or optionallysubstituted heteroaryl is optionally substituted with a substituentselected from F, Cl, Br, I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A),SOR^(A), SO₂R^(A), an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl;

R²³ and R²⁴ are each independently selected from hydrogen, an optionallysubstituted C₁-C₈ alkyl, an optionally substituted C₂-C₈ alkenyl, anoptionally substituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, an optionally substituted C₁-C₈ heteroalkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl, an optionally substituted C₂-C₈heteroalkenyl, an optionally substituted C₂-C₈ alkynyl, an optionallysubstituted C₂-C₈ haloalkynyl, an optionally substituted C₂-C₈heteroalkynyl, an optionally substituted C₂-C₈ heterohaloalkenyl, anoptionally substituted C₂-C₈ heterohaloalkynyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C); or R²³ and R²⁴ together form acarbonyl group, provided that if R¹⁸ is NO₂ and X is NH, then R²³ andR²⁴ do not together form a carbonyl group; or

R²² and R²³ are optionally linked to form a ring; or

R²³ and R²⁵ are optionally linked to form a ring;

R²⁵ is selected from a halogen, OR^(A), NR^(A)R^(B), hydrogen, anoptionally substituted C₁-C₈ alkyl, an optionally substituted C₂-C₈alkenyl, an optionally substituted C₁-C₈ haloalkyl, an optionallysubstituted C₂-C₈ haloalkenyl, an optionally substituted C₁-C₈heteroalkyl, an optionally substituted C₂-C₆ heterohaloalkynyl, anoptionally substituted C₂-C₈ heteroalkenyl, an optionally substitutedC₂-C₈ alkynyl, an optionally substituted C₂-C₈ haloalkynyl, anoptionally substituted C₂-C₈ heterohaloalkenyl, an optionallysubstituted C₂-C₈ heterohaloalkynyl, an optionally substituted C₂-C₈heteroalkynyl, an optionally substituted aryl, an optionally substitutedheteroaryl, and (CH₂)_(m)R^(C);

X is selected from O, S, CR^(A)R^(B), NR^(D), and a bond;

wherein if X is CR^(A)R^(B) or a bond, then R²⁵ and R²⁶ are eachindependently selected from a halogen, OR^(A), NR^(A)R^(B), hydrogen, anoptionally substituted C₁-C₈ alkyl, an optionally substituted C₂-C₈alkenyl, an optionally substituted C₁-C₈ haloalkyl, an optionallysubstituted C₂-C₈ haloalkenyl, an optionally substituted C₁-C₈heteroalkyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ heterohaloalkenyl, an optionallysubstituted C₂-C₆ heterohaloalkynyl, an optionally substituted C₂-C₈heteroalkenyl, an optionally substituted C₂-C₈ alkynyl, an optionallysubstituted C₂-C₈ haloalkynyl, an optionally substituted C₂-C₈heteroalkynyl, an optionally substituted aryl, an optionally substitutedheteroaryl, and (CH₂)_(m)R^(C); or R²⁵ and R²⁶ together form a carbonylgroup;

and wherein if X is O, S, or NR^(D), then R²⁵ and R¹⁶ are eachindependently selected from hydrogen, an optionally substituted C₁-C₈alkyl, an optionally substituted C₂-C₈ alkenyl, an optionallysubstituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, an optionally substituted C₁-C₈ heteroalkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl, an optionally substituted C₂-C₆heterohaloalkenyl, an optionally substituted C₂-C₆ heterohaloalkynyl, anoptionally substituted C₂-C₈ heteroalkenyl, an optionally substitutedC₂-C₈ alkynyl, an optionally substituted C₂-C₈ haloalkynyl, anoptionally substituted C₂-C₈ heteroalkynyl, an optionally substitutedaryl, an optionally substituted heteroaryl, and (CH₂)_(m)R^(C); or R²⁵and R²⁶ together form a carbonyl group;

R^(A) and R^(B) are each independently selected from hydrogen, anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, and an optionally substituted C₁-C₄ heteroalkyl;

R^(C) is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl that is optionally with a substituent selectedfrom F, Cl, Br, I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A),SO₂R^(A), an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl;

R^(D) is selected from hydrogen, an optionally substituted C₁-C₄ alkyl,an optionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl;

Z is selected from O, S, CR^(A)R^(B), and NR^(D);

n is 0, 1, or 2; and

m is 1 or 2.

In other embodiments, the compounds have formula:

wherein the variables are as described elsewhere herein.

In other embodiments, the compounds have formula:

wherein the variables are as described elsewhere herein.

In other embodiments, R¹⁸ and R¹⁹ are each independently selected fromhydrogen, F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, anoptionally substituted C₁-C₄ heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B),COR^(A), CO₂R^(A), CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B);

R²³ and R²⁴ are each independently selected from hydrogen, an optionallysubstituted C₁-C₈ alkyl, an optionally substituted C₂-C₈ alkenyl, anoptionally substituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, an optionally substituted C₁-C₈ heteroalkyl, an optionallysubstituted C₂-C₈ heteroalkenyl, an optionally substituted C₂-C₈alkynyl, an optionally substituted C₂-C₈ haloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C); or R²³ and R²⁴ together form acarbonyl group, provided that if R¹⁸ is NO₂ and X is NH, then R²³ andR²⁴ do not together form a carbonyl group; or

R²² and R²³ are optionally linked to form a ring; or

R²³ and R²⁵ are optionally linked to form a ring;

R²⁵ is selected from a halogen, OR^(A), NR^(A)R^(B), hydrogen, anoptionally substituted C₁-C₈ alkyl, an optionally substituted C₂-C₈alkenyl, an optionally substituted C₁-C₈ haloalkyl, an optionallysubstituted C₂-C₈ haloalkenyl, an optionally substituted C₁-C₈heteroalkyl, an optionally substituted C₂-C₈ heteroalkenyl, anoptionally substituted-C₂-C₈ alkynyl, an optionally substituted C₂-C₈haloalkynyl, an optionally substituted C₂-C₈ heteroalkynyl, anoptionally substituted aryl, an optionally substituted heteroaryl, and(CH₂)_(m)R^(C);

X is selected from O, S, CR^(A)R^(B), NR^(D), and a bond;

wherein if X is CR^(A)R^(B) or a bond, then R²⁵ and R²⁶ are eachindependently selected from a halogen, OR^(A), NR^(A)R^(B), hydrogen, anoptionally substituted C₁-C₈ alkyl, an optionally substituted C₂-C₈alkenyl, an optionally substituted C₁-C₈ haloalkyl, an optionallysubstituted C₂-C₈ haloalkenyl, an optionally substituted C₁-C₈heteroalkyl, an optionally substituted C₂-C₈ heteroalkenyl, anoptionally substituted C₂-C₈ alkynyl, an optionally substituted C₂-C₈haloalkynyl, an optionally substituted C₂-C₈ heteroalkynyl, anoptionally substituted aryl, an optionally substituted heteroaryl, and(CH₂)_(m)R^(C); or R²⁵ and R²⁶ together form a carbonyl group;

and wherein if X is O, S, or NR^(D), then R²⁵ and R²⁶ are eachindependently selected from hydrogen, an optionally substituted C₁-C₈alkyl, an optionally substituted C₂-C₈ alkenyl, an optionallysubstituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, an optionally substituted C₁-C₈ heteroalkyl, an optionallysubstituted C₂-C₈ heteroalkenyl, an optionally substituted C₂-C₈alkynyl, an optionally substituted C₂-C₈ haloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, and (CH₂)_(m)R^(C); or R²⁵ and R²⁶together form a carbonyl group;

R^(A) and R^(B) are each independently selected from hydrogen, anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, and an optionally substituted C₁-C₄ heteroalkyl;

R^(C) is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl that is optionally with a substituent selectedfrom F, Cl, Br, I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A),SO₂R^(A), an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl;

R^(D) is selected from hydrogen, an optionally substituted C₁-C₄ alkyl,an optionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl;

Z is selected from O, S, CR^(A)R^(B), and NR^(D);

n is 0, 1, or 2; and

m is 1 or 2.

In other embodiments, R¹⁸ and R¹⁹ are each independently selected fromhydrogen, NO₂, and an optionally substituted C₁-C₄ alkyl; R²² ishydrogen, an optionally substituted C₁-C₄ alkyl and an optionallysubstituted C₁-C₄ haloalkyl; R²³ and R²⁴ are each independently hydrogenor an optionally substituted C₁-C₄ alkyl; and R²⁵ and R²⁶ are eachhydrogen.

In other embodiments, R¹⁸ is NO₂. In other embodiments, R¹⁹ is NO₂. Inother embodiments, R²² is hydrogen or haloalkyl. In other embodiments,R²² is haloalkyl. In other embodiments, R²² is hydrogen or2,2,2-trifluoroethyl. In other embodiments, R²³ and R²⁴ are eachindependently hydrogen or methyl.

In other embodiments, the compounds have formula:

wherein the variables are as described elsewhere herein. In otherembodiments, R¹⁸ and R¹⁹ are each independently selected from hydrogen,NO₂, and an optionally substituted C₁-C₄ alkyl; R²² is hydrogen, anoptionally substituted C₁-C₄ alkyl and an optionally substituted C₁-C₄haloalkyl; R²³ and R²⁴ are each independently hydrogen or an optionallysubstituted C₁-C₄ alkyl; and R²⁵ is hydrogen, an optionally substitutedC₁-C₄ alkyl or alkoxyaryl.

In other embodiments, R¹⁸ is NO₂. In other embodiments, R¹⁹ is NO₂. Inother embodiments, R²² is hydrogen or haloalkyl. In other embodiments,R²² is hydrogen or 2,2,2-trifluoroethyl. In other embodiments, R²³ ishydrogen or methyl. In other embodiments, R²⁵ is hydrogen, methyl ormethoxyphenyl.

Compounds of Formula I

In other embodiments, the compounds have Formula I:

wherein the variables are as described elsewhere herein.

In certain embodiments, R¹ and R² are each independently selected fromhydrogen, F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, anoptionally substituted C₁-C₄ heteroalkyl, COR^(A), CO₂R^(A),CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B), NHCOR^(A), andNHCONR^(A)R^(B), provided that at least one of R¹ and R² is nothydrogen;

R^(3a), R⁴, and R⁵ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl;

wherein if R¹ is NO₂ and R^(3a) is F, then at least one of R² and R⁴ andR⁵ is not hydrogen;

R⁶, R⁷, R¹⁰, and R¹¹ are each independently selected from hydrogen, anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl, an optionally substituted C₂-C₆heterohaloalkenyl, an optionally substituted C₂-C₆ heterohaloalkynyl, anoptionally substituted C₂-C₆ alkynyl, and an optionally substitutedC₂-C₆ alkenyl;

R⁸ and R⁹ are each independently selected from hydrogen, an optionallysubstituted C₁-C₈ alkyl, an optionally substituted C₂-C₈ alkenyl, anoptionally substituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, C₁-C₈ heteroalkyl, an optionally substituted C₂-C₈heteroalkenyl, an optionally substituted C₂-C₈ alkynyl, an optionallysubstituted C₂-C₈ haloalkynyl, an optionally substituted C₂-C₈heteroalkynyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ heterohaloalkenyl, an optionallysubstituted C₂-C₆ heterohaloalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C);

R¹⁴ and R¹⁵ are each independently selected from hydrogen, F, Cl, Br, I,OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B), COR^(A), CO₂R^(A),CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B);

R¹⁶ and R¹⁷ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl;

R^(A) and R^(B) are each independently selected from hydrogen, anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, and an optionally substituted C₁-C₄ heteroalkyl;

R^(C) is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl that is optionally with a substituent selectedfrom F, Cl, Br, I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A),SO₂R^(A), an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl;

R^(D) is selected from hydrogen, an optionally substituted C₁-C₄ alkyl,an optionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl; and

m is 1 or 2.

In certain embodiments, the compounds are selected with a proviso thatat least one of R⁶, R⁷, R¹⁰, and R¹¹ is other than hydrogen and at leastone of R⁸ and R⁹ is other than hydrogen, alkyl, haloalkyl, alkenyl, andalkynyl. In certain embodiments, the compounds are selected with aproviso that at least one of R⁶, R⁷, R¹⁰, and R¹¹ is other than hydrogenand at least one of R⁸ and R⁹ is heterohaloalkyl.

In other embodiments, the compounds provided herein have Formula I,where R¹ is NO₂ or CN; R² is hydrogen, an optionally substituted C₁-C₄alkyl, or an optionally substituted C₁-C₄ haloalkyl; R^(3a) is hydrogenor an optionally substituted C₁-C₄ alkyl; R⁴, R⁶, R⁷, R¹⁰ and R¹¹ areeach hydrogen, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ heterohaloalkenyl or an optionallysubstituted C₂-C₆ heterohaloalkynyl, R⁵ is hydrogen or an optionallysubstituted C₁-C₄ haloalkyl, R⁸ is an optionally substituted C₁-C₄haloalkyl; and R⁹ is an optionally substituted C₁-C₄ haloalkyl.

In other embodiments, the compounds provided herein have Formula I,where R¹IS NO₂ or CN. In other embodiments, R² is hydrogen, halo, anoptionally substituted C₁-C₄ alkyl, or an optionally substituted C₁-C₄haloalkyl. In other embodiments, R^(3a) is hydrogen or an optionallysubstituted C₁-C₄ alkyl. In other embodiments, R⁴, R⁶, R⁷, R¹⁰ and R¹¹are each hydrogen. In other embodiments, R⁵ is hydrogen or an optionallysubstituted C₁-C₄ haloalkyl. In other embodiments, R⁸ is an optionallysubstituted C₁-C₄ haloalkyl. In other embodiments, R⁹ is an optionallysubstituted C₁-C₄ haloalkyl.

In other embodiments, R² is hydrogen, chloro, methyl or trifluoromethyl.In other embodiments, R^(3a) is hydrogen or methyl. In otherembodiments, R⁵ is hydrogen or trifluoromethyl. In other embodiments, R⁸is 2,2,2-trifluoroethyl. In other embodiments, R⁹ is2,2,2-trifluoroethyl.

Compounds of Formula III

In other embodiments, the compounds have Formula III:

wherein the variables are as described elsewhere herein.

In other embodiments, the compounds provided herein have Formula I,where R¹ and R² are each independently selected from hydrogen, F, Cl,Br, I, OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl,an optionally substituted C₁-C₄ haloalkyl, an optionally substitutedC₁-C₄ heteroalkyl, COR^(A), CO₂R^(A), CONR^(A)R^(B), SOR^(A), SO₂R^(A),and SO₂NR^(A)R^(B), NHCOR^(A), and NHCONR^(A)R^(B), provided that atleast one of R¹ and R² is not hydrogen;

R^(3a), R⁴, and R⁵ are each independently selected from hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl;

wherein if R¹ is NO₂ and R^(3a) is F, then at least one of R² and R⁴ andR⁵ is not hydrogen;

R⁶, R⁷, R¹⁰, and R¹¹ are each independently selected from hydrogen, anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl, an optionally substituted C₂-C₆heterohaloalkenyl, an optionally substituted C₂-C₆ heterohaloalkynyl, anoptionally substituted C₂-C₆ alkynyl, and an optionally substitutedC₂-C₆ alkenyl;

R⁸ and R⁹ are each independently selected from hydrogen, an optionallysubstituted C₁-C₈ alkyl, an optionally substituted C₂-C₈ alkenyl, anoptionally substituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, C₁-C₈ heteroalkyl, an optionally substituted C₂-C₈heteroalkenyl, an optionally substituted C₂-C₈ alkynyl, an optionallysubstituted C₂-C₈ haloalkynyl, an optionally substituted C₂-C₈heteroalkynyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ heterohaloalkenyl, an optionallysubstituted C₂-C₆ heterohaloalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C);

R¹⁴ and R¹⁵ are each independently selected from hydrogen, F, Cl, Br, I,OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B), COR^(A), CO₂R^(A),CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B);

R¹⁶ and R¹⁷ are each independently selected from hydrogen, F, Cl, OR⁴,an optionally substituted C₁-C₄ alkyl, and an optionally substitutedC₁-C₄ haloalkyl;

R^(A) and R^(B) are each independently selected from hydrogen, anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, and an optionally substituted C₁-C₄ heteroalkyl;

R^(C) is selected from an optionally substituted aryl and an optionallysubstituted heteroaryl that is optionally with a substituent selectedfrom F, Cl, Br, I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A),SO₂R^(A), an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl;

R^(D) is selected from hydrogen, an optionally substituted C₁-C₄ alkyl,an optionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl; and

m is 1 or 2.

In certain embodiments, the compounds of Formula III are selected with aproviso that at least one of R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ is selectedfrom an optionally substituted C₁-C₆ heteroalkyl. In certainembodiments, the compounds of Formula III are selected with a provisothat at least one of R⁶, R⁷, R¹⁰, and R¹¹ is other than hydrogen. Incertain embodiments, the compounds of Formula III are selected with aproviso that at least one of R⁶, R⁷, R¹⁰, and R¹¹ is other than hydrogenand at least one of R⁸ and R⁹ is other than hydrogen, alkyl, haloalkyl,alkenyl, and alkynyl. In certain embodiments, the compounds are selectedwith a proviso that at least one of R⁶, R⁷, R¹⁰, and R¹¹ is other thanhydrogen and at least one of R⁸ and R⁹ is heterohaloalkyl.

In embodiments in which two or more of a particular variable arepresent, the identities of those two or more particular variables areselected independently and, thus, may be the same or different from oneanother. For example, certain compounds provided herein contain two ormore R^(A) groups. The identities of those two or more R^(A) groups areeach selected independently. Thus, in certain embodiments, those R^(A)groups are all the same as one another; in certain embodiments, thoseR^(A) groups are all different from one another; and in certainembodiments, some of those R^(A) groups are the same as one another andsome are different from one another.

In certain embodiments, a compound of Formula I, Formula II, FormulaIII, Formula IV, Formula V, or Formula VI is a selective androgenreceptor modulator. In certain embodiments, a compound of Formula I is aselective androgen receptor agonist. In certain embodiments, a compoundof Formula I, Formula II, Formula III, Formula IV, Formula V, or FormulaVI is a selective androgen receptor antagonist. In certain embodiments,a compound of Formula I, Formula II, Formula III, Formula IV, Formula V,or Formula VI is a selective androgen receptor partial agonist. Incertain embodiments, a compound of Formula I, Formula II, Formula III,Formula IV, Formula V, or Formula VI is a tissue-specific selectiveandrogen modulator. In certain embodiments, a compound of Formula I,Formula II, Formula III, Formula IV, Formula V, or Formula VI is agene-specific selective androgen modulator. In certain embodiments, acompound of Formula I, Formula II, Formula III, Formula IV, Formula V,or Formula VI is a selective androgen receptor binding compound.

In certain embodiments, provided herein is a compound selected from:

-   N,N-bis(2,2,2-trifluoroethyl)-3-methyl-4-nitroaniline (compound    101);-   N,N-bis(2,2,2-trifluoroethyl)-4-nitroaniline (compound 102);-   4-Bromo-N,N-bis(2,2,2-trifluoroethyl)-3-(trifluoromethyl)aniline    (compound 103^(a));-   4-(Bis(2,2,2-trifluoroethyl)amino)-2-(trifluoromethyl)benzonitrile    (compound 103);-   (5R)—N-(4-nitrophenyl)-5-(dimethyl-tort-butylsilyloxymethyl)-2-pyrrolidone    (compound 104);-   (5R)—N-(4-nitrophenyl)-5-(hydroxymethyl)-2-pyrrolidone (compound    105);-   (2R)—N-(4-nitro-3-trifluoromethylphenyl)-2-(dimethyl-tert-butylsilyloxymethyl)pyrrolidine    (compound 106);-   (2R)—N-(4-nitro-3-trifluoromethylphenyl)-2-(hydroxymethyl)pyrrolidine    (compound 108);-   (2R)—N-(4-nitrophenyl)-2-(hydroxymethyl)pyrrolidine (compound 109);-   (2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine    (compound 110);-   (2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine    (compound 111);-   (2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine    (compound 112);-   (2S)—N-(4-nitrophenyl)-2-(hydroxymethyl)pyrrolidine (compound 113);-   (2R)—N-(4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine    (compound 114);-   (2R)—N-(4-nitrophenyl)-2-(R)-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine    (compound 115);-   (2S)—N-(4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine    (compound 116);-   (2S)—N-(4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine    (compound 117);-   3-(3-Methoxyphenyl)-6-nitro-2,7-dimethyl-1H-indole (compound 118);-   4-[Bis-(2,2,2-trifluoroethyl)amino]-2-chloro-3-methyl-benzonitrile    (compound 119);-   cis-2,5-Dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine    (compound 120);-   trans-2,5-dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine    (compound 121);-   1-(4-Nitro-3-trifluoromethylphenyl)-piperidine-2-carboxylic acid    ethyl ester (compound 122);-   1-(4-Nitro-3-trifluoromethylphenyl)-4-(hydroxymethyl)-piperidine    (compound 123);-   (1-(3-trifluoromethyl-4-nitrophenyl)piperidin-2-yl)methyl acetate    (compound 124);-   4-(2-Hydroxymethyl-pyrrolidin-1-yl)-benzonitrile (compound 125);-   4-Benzyl-2-hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine    (compound 126);-   2-Fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-benzonitrile (compound    127);-   4-Hydroxy-1-(4-nitrophenyl)-pyrrolidine-2-carboxylic acid ethyl    ester (compound 128);-   4-Hydroxy-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine-2-carboxylic    acid ethyl ester (compound 129);-   5-Hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidin-3-ol    (compound 130);-   2-(Aminomethyl)-1-(4-Nitro-3-trifluoromethylphenyl)-pyrrolidine    (compound 131);-   4-Hydroxy-1-(4-nitrophenyl)-pyrrolidine-2-carboxylic acid (compound    132); and-   4-Hydroxy-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine-2-carboxylic    acid (compound 133); or pharmaceutically acceptable salts, esters,    amides, and prodrugs thereof.

In other embodiments, provided herein is a compound selected from:N,N′-bis(2,2,2-trifluoroethyl)-3-methyl-4-nitroaniline;N,N′-bis(2,2,2-trifluoroethyl)-4-nitroaniline;5-(2,2,2-trifluoroethyl)amino-2-bromobenzotrifluoride;4-N,N′-bis(2,2,2-trifluoroethyl)amino-2-trifluoromethylbenzonitrile;(R)—N-4-nitrophenyl-5-(dimethyl-tert-butylsilyloxymethyl)-2-pyrrolidone;(R)—N-4-nitrophenyl-5-hydroxymethyl-2-pyrrolidone;(R)—N-(4-nitro-3-trifluoromethylphenyl)-2-dimethyl-tert-butylsilyloxymethylpyrrolidine;(R)—N-(4-nitro-3-trifluoromethylphenyl)-2-hydroxymethylpyrrolidine;(R)—N-(4-nitrophenyl)-2-hydroxymethylpyrrolidine;(R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine;N-(3-Trifluoromethyl-4-nitrophenyl)-2-(R)-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;N-(3-Trifluoromethyl-4-nitrophenyl)-2-(R)-(1-(R)—hydroxy-2,2,2-trifluoroethyl)pyrrolidine;(S)—N-(4-nitrophenyl)-2-hydroxymethylpyrrolidine;N-(4-nitrophenyl)-2-(R)-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;N-(4-nitrophenyl)-2-(R)-(1-(R)-hydroxy-2,2,2-trifluoroethyl);N-(4-nitrophenyl)-2-(S)-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;andN-(4-nitrophenyl)-2-(S)-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;and a pharmaceutically acceptable salt, ester, amide, or prodrug of anyof those compounds.

Certain compounds provided herein can exist as stereoisomers includingoptical isomers. The present disclosure is intended to include allstereoisomers and both the racemic mixtures of such stereoisomers aswell as the individual enantiomers that can be separated according tomethods that are known in the art.

C. Preparation of the Compounds

In certain embodiments, of the compounds provided herein can besynthesized using the following synthesis schemes. In each of theSchemes the R groups correspond to the definitions described above.

Scheme I describes the alkylation of the substituted anilines such asStructure 1. Reductive alkylation of the substituted anilines (e.g.,Structure 1) with an aldehyde or ketone or acid in the presence of areducing agent, such as sodium cyanoborohydride or sodium borohydrideaffords compounds of Structure 2. Alternatively, treatment of thesubstituted anilines of Structure 1 with an organohalide in the presenceof a base provides the compounds of Structure 2.

Scheme II describes the preparation of compounds of Structure 5 from thesubstituted aryl halides such as Structure 3. Palladium catalyzedcoupling reaction of Structure 3 and compounds of Structure 4 providethe products of Structure 5.

Scheme III describes the indole synthesis from substituted anilines suchas Structure 6. Diazotization of the substituted anilines (e.g.,Structure 6) followed by treatment with a reducing agent, such tindichloride affords the corresponding hydrazine. Treatment of thehydrazines with a ketone, such as Structure 7, under acidic conditionsaffords the indoles of Structure 8.

Scheme IV describes the substitution reaction of aromatic fluorides ofStructure 9 with amines such as Structure 10 to give compounds ofStructure 11.

Scheme V describes the substitution reaction of aromatic fluorides ofStructure 12 with amino alcohols to give compounds of Structure 13.Alkylation of the nitrogen atom, followed by cyclization gives thesubstituted benzoxazines of Structure 14.

Scheme V describes the synthesis of indoles of structure 16, fromhydrazines such as 15. Alkylation of the nitrogen atom under reductiveconditions gives the indolines of Structure 17. These can be oxidized tothe N-alkylated indoles of Structure 18.

Scheme VII describes the nitration reaction of fused heterocyclicaromatics of Structure 19 with nitric acid to give compounds ofStructure 20.

In certain embodiments, provided herein is a salt corresponding to anyof the compounds provided herein. In certain embodiments, the saltcorresponding to a selective androgen receptor modulator or selectiveandrogen binding agent is provided herein. In certain embodiments, asalt is obtained by reacting a compound with an inorganic acid, such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. In certainembodiments, a salt is obtained by reacting a compound with a base toform a salt such as an ammonium salt, an alkali metal salt, such as asodium or a potassium salt, an alkaline earth metal salt, such as acalcium or a magnesium salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)-methylamine, and salts with amino acids such asarginine, lysine, and the like.

In certain embodiments, one or more carbon atoms of a compound providedherein is replaced with silicon. See e.g., WO 03/037905A1; Tacke andZilch, Endeavour, New Series, 10, 191-197 (1986); Bains and Tacke, Curr.Opin. Drug Discov Devel. July:6(4):526-43 (2003). In certainembodiments, compounds provided herein containing one or more siliconatoms possess certain desired properties, including, but not limited to,greater stability and/or longer half-life in a patient, when compared tothe same compound in which none of the carbon atoms have been replacedwith a silicon atom.

D. Formulation of Pharmaceutical Compositions

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of the androgen receptor activitymodulators provided herein that are useful in the prevention, treatment,or amelioration of one or more of the symptoms of diseases or disordersassociated with androgen receptor activity. Such prevention, treatment,or amelioration of diseases or disorders include, but are not limitedto, maintenance of muscle strength and function (e.g., in the elderly);reversal or prevention of frailty or age-related functional decline(“ARFD”) in the elderly (e.g., sarcopenia); treatment of catabolic sideeffects of glucocorticoids; prevention and/or treatment of reduced bonemass, density or growth (e.g., osteoporosis and osteopenia); treatmentof chronic fatigue syndrome (CFS); chronic myalgia; treatment of acutefatigue syndrome and muscle loss following elective surgery (e.g.,post-surgical rehabilitation); accelerating of wound healing;accelerating bone fracture repair (such as accelerating the recovery ofhip fracture patients); accelerating healing of complicated fractures,e.g. distraction osteogenesis; in joint replacement; prevention ofpost-surgical adhesion formation; acceleration of tooth repair orgrowth; maintenance of sensory function (e.g., hearing, sight,olefaction and taste); treatment of periodontal disease; treatment ofwasting secondary to fractures and wasting in connection with chronicobstructive pulmonary disease (COPD), chronic liver disease, AIDS,weightlessness, cancer cachexia, burn and trauma recovery, chroniccatabolic state (e.g., coma), eating disorders (e.g., anorexia) andchemotherapy; treatment of cardiomyopathy; treatment ofthrombocytopenia; treatment of growth retardation in connection withCrohn's disease; treatment of short bowel syndrome; treatment ofirritable bowel syndrome; treatment of inflammatory bowel disease;treatment of Crohn's disease and ulcerative colits; treatment ofcomplications associated with transplantation; treatment ofphysiological short stature including growth hormone deficient childrenand short stature associated with chronic illness; treatment of obesityand growth retardation associated with obesity; treatment of anorexia(e.g., associated with cachexia or aging); treatment of hypercortisolismand Cushing's syndrome; Paget's disease; treatment of osteoarthritis;induction of pulsatile growth hormone release; treatment ofosteochondrodysplasias; treatment of depression, nervousness,irritability and stress; treatment of reduced mental energy and lowself-esteem (e.g., motivation/assertiveness); improvement of cognitivefunction (e.g., the treatment of dementia, including Alzheimer's diseaseand short term memory loss); treatment of catabolism in connection withpulmonary dysfunction and ventilator dependency; treatment of cardiacdysfunction (e.g., associated with valvular disease, myocardialinfarction, cardiac hypertrophy or congestive heart failure); loweringblood pressure; protection against ventricular dysfunction or preventionof reperfusion events; treatment of adults in chronic dialysis; reversalor slowing of the catabolic state of aging; attenuation or reversal ofprotein catabolic responses following trauma (e.g., reversal of thecatabolic state associated with surgery, congestive heart failure,cardiac myopathy, burns, cancer, COPD etc.); reducing cachexia andprotein loss due to chronic illness such as cancer or AIDS; treatment ofhyperinsulinemia including nesidioblastosis; treatment ofimmunosuppressed patients; treatment of wasting in connection withmultiple sclerosis or other neurodegenerative disorders; promotion ofmyelin repair; maintenance of skin thickness; treatment of metabolichomeostasis and renal homeostasis (e.g., in the frail elderly);stimulation of osteoblasts, bone remodeling and cartilage growth;regulation of food intake; treatment of insulin resistance, includingNIDDM, in mammals (e.g., humans); treatment of insulin resistance in theheart; improvement of sleep quality and correction of the relativehyposomatotropism of senescence due to high increase in REM sleep and adecrease in REM latency; treatment of hypothermia; treatment ofcongestive heart failure; treatment of lipodystrophy (e.g., in patientstaking HIV or AIDS therapies such as protease inhibitors); treatment ofmuscular atrophy (e.g., due to physical inactivity, bed rest or reducedweight-bearing conditions); treatment of musculoskeletal impairment(e.g., in the elderly); improvement of the overall pulmonary function;treatment of sleep disorders; and the treatment of the catabolic stateof prolonged critical illness; treatment of hirsutism, acne, seborrhea,androgenic alopecia, anemia, hyperpilosity, benign prostate hypertrophy,adenomas and neoplasies of the prostate (e.g., advanced metastaticprostate cancer) and malignant tumor cells containing the androgenreceptor, such as is the case for breast, brain, skin, ovarian, bladder,lymphatic, liver and kidney cancers; cancers of the skin, pancreas,endometrium, lung and colon; osteosarcoma; hypercalcemia of malignancy;metastatic bone disease; treatment of spermatogenesis, endometriosis andpolycystic ovary syndrome; conteracting preeclampsia, eclampsia ofpregnancy and preterm labor; treatment of premenstural syndrome;treatment of vaginal dryness; age related decreased testosterone levelsin men, male menopause, hypogonadism, male hormone replacement, male andfemale sexual dysfunction (e.g., erectile dysfunction, decreased sexdrive, sexual well-being, decreased libido), male and femalecontraception, hair loss, Reaven's Syndrome and the enhancement of boneand muscle performance/strength.

The compositions contain one or more compounds provided herein. Thecompounds are formulated into suitable pharmaceutical preparations suchas solutions, suspensions, tablets, dispersible tablets, pills,capsules, powders, sustained release formulations or elixirs, for oraladministration or in sterile solutions or suspensions for parenteraladministration, as well as transdermal patch preparation and dry powderinhalers. Typically the compounds described above are formulated intopharmaceutical compositions using techniques and procedures well knownin the art (see, e.g., Ansel Introduction to Pharmaceutical DosageForms, Fourth Edition 1985, 126).

In certain embodiments, a pharmaceutical composition containing one ormore compounds provided herein is prepared using known techniques,including, but not limited to mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping ortabletting processes.

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable derivatives is (are) mixed with asuitable pharmaceutical carrier or vehicle. The compounds can bederivatized as the corresponding salts, esters, enol ethers or esters,acids, bases, solvates, hydrates or prodrugs prior to formulation, asdescribed above. The concentrations of the compounds in the compositionsare effective for delivery of an amount, upon administration, thattreats, prevents, or ameliorates one or more of the symptoms of diseasesor disorders associated with androgen activity or in which androgenactivity is implicated. Such prevention, treatment, or ameliorationdiseases or disorders include, but are not limited to, maintenance ofmuscle strength and function (e.g., in the elderly); reversal orprevention of frailty or age-related functional decline (“ARFD”) in theelderly (e.g., sarcopenia); treatment of catabolic side effects ofglucocorticoids; prevention and/or treatment of reduced bone mass,density or growth (e.g., osteoporosis and osteopenia); treatment ofchronic fatigue syndrome (CFS); chronic myalgia; treatment of acutefatigue syndrome and muscle loss following elective surgery (e.g.,post-surgical rehabilitation); accelerating of wound healing;accelerating bone fracture repair (such as accelerating the recovery ofhip fracture patients); accelerating healing of complicated fractures,e.g. distraction osteogenesis; in joint replacement; prevention ofpost-surgical adhesion formation; acceleration of tooth repair orgrowth; maintenance of sensory function (e.g., hearing, sight,olefaction and taste); treatment of periodontal disease; treatment ofwasting secondary to fractures and wasting in connection with chronicobstructive pulmonary disease (COPD), chronic liver disease, AIDS,weightlessness, cancer cachexia, burn and trauma recovery, chroniccatabolic state (e.g., coma), eating disorders (e.g., anorexia) andchemotherapy; treatment of cardiomyopathy; treatment ofthrombocytopenia; treatment of growth retardation in connection withCrohn's disease; treatment of short bowel syndrome; treatment ofirritable bowel syndrome; treatment of inflammatory bowel disease;treatment of Crohn's disease and ulcerative colits; treatment ofcomplications associated with transplantation; treatment ofphysiological short stature including growth hormone deficient childrenand short stature associated with chronic illness; treatment of obesityand growth retardation associated with obesity; treatment of anorexia(e.g., associated with cachexia or aging); treatment of hypercortisolismand Cushing's syndrome; Paget's disease; treatment of osteoarthritis;induction of pulsatile growth hormone release; treatment ofosteochondrodysplasias; treatment of depression, nervousness,irritability and stress; treatment of reduced mental energy and lowself-esteem (e.g., motivation/assertiveness); improvement of cognitivefunction (e.g., the treatment of dementia, including Alzheimer's diseaseand short term memory loss); treatment of catabolism in connection withpulmonary dysfunction and ventilator dependency; treatment of cardiacdysfunction (e.g., associated with valvular disease, myocardialinfarction, cardiac hypertrophy or congestive heart failure); loweringblood pressure; protection against ventricular dysfunction or preventionof reperfusion events; treatment of adults in chronic dialysis; reversalor slowing of the catabolic state of aging; attenuation or reversal ofprotein catabolic responses following trauma (e.g., reversal of thecatabolic state associated with surgery, congestive heart failure,cardiac myopathy, burns, cancer, COPD etc.); reducing cachexia andprotein loss due to chronic illness such as cancer or AIDS; treatment ofhyperinsulinemia including nesidioblastosis; treatment ofimmunosuppressed patients; treatment of wasting in connection withmultiple sclerosis or other neurodegenerative disorders; promotion ofmyelin repair; maintenance of skin thickness; treatment of metabolichomeostasis and renal homeostasis (e.g., in the frail elderly);stimulation of osteoblasts, bone remodeling and cartilage growth;regulation of food intake; treatment of insulin resistance, includingNIDDM, in mammals (e.g., humans); treatment of insulin resistance in theheart; improvement of sleep quality and correction of the relativehyposomatotropism of senescence due to high increase in REM sleep and adecrease in REM latency; treatment of hypothermia; treatment ofcongestive heart failure; treatment of lipodystrophy (e.g., in patientstaking HIV or AIDS therapies such as protease inhibitors); treatment ofmuscular atrophy (e.g., due to physical inactivity, bed rest or reducedweight-bearing conditions); treatment of musculoskeletal impairment(e.g., in the elderly); improvement of the overall pulmonary function;treatment of sleep disorders; and the treatment of the catabolic stateof prolonged critical illness; treatment of hirsutism, acne, seborrhea,androgenic alopecia, anemia, hyperpilosity, benign prostate hypertrophy,adenomas and neoplasies of the prostate (e.g., advanced metastaticprostate cancer) and malignant tumor cells containing the androgenreceptor, such as is the case for breast, brain, skin, ovarian, bladder,lymphatic, liver and kidney cancers; cancers of the skin, pancreas,endometrium, lung and colon; osteosarcoma; hypercalcemia of malignancy;metastatic bone disease; treatment of spermatogenesis, endometriosis andpolycystic ovary syndrome; conteracting preeclampsia, eclampsia ofpregnancy and preterm labor; treatment of premenstural syndrome;treatment of vaginal dryness; age related decreased testosterone levelsin men, male menopause, hypogonadism, male hormone replacement, male andfemale sexual dysfunction (e.g., erectile dysfunction, decreased sexdrive, sexual well-being, decreased libido), male and femalecontraception, hair loss, Reaven's Syndrome and the enhancement of boneand muscle performance/strength.

Typically, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds can be formulated as the solepharmaceutically active ingredient in the composition or can be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, such as tumor-targeted liposomes, can also besuitable as pharmaceutically acceptable carriers. These can be preparedaccording to methods known to those skilled in the art. For example,liposome formulations can be prepared as described in U.S. Pat. No.4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV's) canbe formed by drying down egg phosphatidyl choline and brain phosphatidylserine (7:3 molar ratio) on the inside of a flask. A solution of acompound provided herein in phosphate buffered saline lacking divalentcations (PBS) is added and the flask shaken until the lipid film isdispersed. The resulting vesicles are washed to remove unencapsulatedcompound, pelleted by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, inactivation and excretion rates of theactive compound, the physicochemical characteristics of the compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art. For example, the amount that isdelivered is sufficient to ameliorate one or more of the symptoms ofdiseases or disorders associated with androgen activity or in whichandrogen activity is implicated, as described herein.

The effective amount of a compound provided herein can be determined byone of ordinary skill in the art, and includes exemplary dosage amountsfor a mammal of from about 0.05 to 100 mg/kg of body weight of activecompound per day, which can be administered in a single dose or in theform of individual divided doses, such as from 1 to 4 times per day. Itwill be understood that the specific dose level and frequency of dosagefor any particular subject can be varied and will depend upon a varietyof factors, including the activity of the specific compound employed,the metabolic stability and length of action of that compound, thespecies, age, body weight, general health, sex and diet of the subject,the mode and time of administration, rate of excretion, drugcombination, and severity of the particular condition.

The active ingredient can be administered at once, or can be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and can be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuescan also vary with the severity of the condition to be alleviated.

It is to be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the compounds, compositions,methods and other subject matter provided herein.

Pharmaceutically acceptable derivatives include acids, bases, enolethers and esters, salts, esters, hydrates, solvates and prodrug forms.The derivative is selected such that its pharmacokinetic properties aresuperior to the corresponding neutral compound.

Thus, effective concentrations or amounts of one or more of thecompounds described herein or pharmaceutically acceptable derivativesthereof are mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating one or more symptoms of, or for treating or preventingdiseases or disorders associated with androgen receptor activity or inwhich androgen receptor activity is implicated, as described herein. Theconcentration of active compound in the composition will depend onabsorption, inactivation, excretion rates of the active compound, thedosage schedule, amount administered, particular formulation as well asother factors known to those of skill in the art.

The compositions are intended to be administered by a suitable route,including orally in form of capsules, tablets, granules, powders orliquid formulations including syrups; parenterally, such assubcutaneously, intravenously, intramiscularly, with inteasternalinjection or infusion techniques (as sterile injectable aq. or non-aq.solutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; liposomally; and locally. The compositionscan be in liquid, semi-liquid or solid form and are formulated in amanner suitable for each route of administration. In certainembodiments, administration of the formulation include parenteral andoral modes of administration. In one embodiment, the compositions areadministered orally.

In certain embodiments, the pharmaceutical compositions provided hereincontaining one or more compounds provided herein is a solid (e.g., apowder, tablet, and/or capsule). In certain of such embodiments, a solidthe pharmaceutical composition containing one or more compounds providedherein is prepared using ingredients known in the art, including, butnot limited to, starches, sugars, diluents, granulating agents,lubricants, binders, and disintegrating agents.

In certain embodiments, a pharmaceutical composition containing one ormore compounds provided herein is formulated as a depot preparation.Certain of such depot preparations are typically longer acting thannon-depot preparations. In certain embodiments, such preparations areadministered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. In certain embodiments,depot preparations are prepared using suitable polymeric or hydrophobicmaterials (for example an emulsion in an acceptable oil) or ion exchangeresins, or as sparingly soluble derivatives, for example, as a sparinglysoluble salt.

In certain embodiments, a pharmaceutical composition containing one ormore compounds provided herein contains a delivery system. Examples ofdelivery systems include, but are not limited to, liposomes andemulsions. Certain delivery systems are useful for preparing certainpharmaceutical compositions including those containing hydrophobiccompounds. In certain embodiments, certain organic solvents such asdimethylsulfoxide are used.

In certain embodiments, a pharmaceutical composition containing one ormore compounds provided herein contains one or more tissue-specificdelivery molecules designed to deliver the pharmaceutical composition tospecific tissues or cell types. For example, in certain embodiments,pharmaceutical compositions include liposomes coated with atissue-specific antibody.

In certain embodiments, a pharmaceutical composition containing one ormore compounds provided herein contains a co-solvent system. Certain ofsuch co-solvent systems contain, for example, benzyl alcohol, a nonpolarsurfactant, a water-miscible organic polymer, and an aqueous phase. Incertain embodiments, such co-solvent systems are used for hydrophobiccompounds. A non-limiting example of such a co-solvent system is the VPDco-solvent system, which is a solution of absolute ethanol containing 3%w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™,and 65% w/v polyethylene glycol 300. The proportions of such co-solventsystems may be varied considerably without significantly altering theirsolubility and toxicity characteristics. Furthermore, the identity of cosolvent components may be varied: for example, other surfactants may beused instead of Polysorbate 80™; the fraction size of polyethyleneglycol may be varied; other biocompatible polymers may replacepolyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars orpolysaccharides may substitute for dextrose.

In certain embodiments, solutions or suspensions used for parenteral,intradermal, subcutaneous, or topical application can include any of thefollowing components: a sterile diluent, such as water for injection,saline solution, fixed oil, polyethylene glycol, glycerine, propyleneglycol or other synthetic solvent; antimicrobial agents, such as benzylalcohol and methyl parabens; antioxidants, such as ascorbic acid andsodium bisulfite; chelating agents, such as ethylenediaminetetraaceticacid (EDTA); buffers, such as acetates, citrates and phosphates; andagents for the adjustment of tonicity such as sodium chloride ordextrose. Parenteral preparations can be enclosed in ampules, disposablesyringes or single or multiple dose vials made of glass, plastic orother suitable material.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds can be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as TWEEN®, or dissolution in aqueous sodium bicarbonate.Derivatives of the compounds, such as prodrugs of the compounds can alsobe used in formulating effective pharmaceutical compositions.

In certain embodiments, a pharmaceutical composition containing one ormore compounds provided herein contains a sustained-release system. Anon-limiting example of such a sustained-release system is asemipermeable matrix of solid hydrophobic polymers. In certainembodiments, sustained release systems may, depending on their chemicalnature, release compounds over a period of hours, days, weeks or months.

In certain embodiments, upon mixing or addition of the compound(s), theresulting mixture can be a solution, suspension, emulsion or the like.The form of the resulting mixture depends upon a number of factors,including the intended mode of administration and the solubility of thecompound in the selected carrier or vehicle. The effective concentrationis sufficient for ameliorating the symptoms of the disease, disorder orcondition treated and can be empirically determined.

The pharmaceutical compositions are provided for administration tohumans and animals in unit dosage forms, such as tablets, capsules,pills, powders, granules, sterile parenteral solutions or suspensions,and oral solutions or suspensions, and oil-water emulsions containingsuitable quantities of the compounds or pharmaceutically acceptablederivatives thereof. The pharmaceutically active compounds andderivatives thereof are typically formulated and administered inunit-dosage forms or multiple-dosage forms. Unit-dose forms as usedherein refers to physically discrete units suitable for human and animalsubjects and packaged individually as is known in the art. Eachunit-dose contains a predetermined quantity of the therapeuticallyactive compound sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carrier, vehicle ordiluent. Examples of unit-dose forms include ampoules and syringes andindividually packaged tablets or capsules. Unit-dose forms can beadministered in fractions or multiples thereof. A multiple-dose form isa plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dose form. Examples ofmultiple-dose forms include vials, bottles of tablets or capsules orbottles of pints or gallons. Hence, multiple dose form is a multiple ofunit-doses which are not segregated in packaging.

The composition can contain along with the active ingredient: a diluentsuch as lactose, sucrose, dicalcium phosphate, orcarboxymethylcellulose; a lubricant, such as magnesium stearate, calciumstearate and talc; and a binder such as starch, natural gums, such asgum acaciagelatin, glucose, molasses, polyinylpyrrolidine, cellulosesand derivatives thereof, povidone, crospovidones and other such bindersknown to those of skill in the art. Liquid pharmaceuticallyadministrable compositions can, for example, be prepared by dissolving,dispersing, or otherwise mixing an active compound as defined above andoptional pharmaceutical adjuvants in a carrier, such as, for example,water, saline, aqueous dextrose, glycerol, glycols, ethanol, and thelike, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered can also contain minoramounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, or solubilizing agents, pH buffering agents and thelike, for example, acetate, sodium citrate, cyclodextrin derivatives,sorbitan monolaurate, triethanolamine sodium acetate, triethanolamineoleate, and other such agents. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 15th Edition, 1975. The composition or formulationto be administered will, in any event, contain a quantity of the activecompound in an amount sufficient to alleviate the symptoms of thetreated subject.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from non-toxic carrier can beprepared. For oral administration, a pharmaceutically acceptablenon-toxic composition is formed by the incorporation of any of thenormally employed excipients, such as, for example pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions can contain 0.001%-100% activeingredient, in one embodiment 0.1-85%, in another embodiment 75-95%.

In certain embodiments, the compounds can be administered in a formsuitable for immediate release or extended release. Immediate release orextended release can be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps. Exemplarycompositions for topical administration include a topical carrier suchas PLASTIBASE® (mineral oil gelled with polyethylene).

In certain embodiments, compounds used in the pharmaceuticalcompositions may be provided as pharmaceutically acceptable salts withpharmaceutically compatible counterions. Pharmaceutically compatiblesalts may be formed with many acids, including but not limited tohydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaricacid, malic acid, succinic acid, etc.

In certain embodiments, the pharmaceutical compositions contain acompound provided herein in a therapeutically effective amount. Incertain embodiments, the therapeutically effective amount is sufficientto prevent, alleviate or ameliorate symptoms of a disease or to prolongthe survival of the subject being treated. Determination of atherapeutically effective amount is well within the capability of thoseskilled in the art.

The compositions can include other active compounds to obtain desiredcombinations of properties. The compounds provided herein, orpharmaceutically acceptable derivatives thereof as described herein, canalso be advantageously administered for therapeutic or prophylacticpurposes together with another pharmacological agent known in thegeneral art to be of value in treating one or more of the diseases ormedical conditions referred to hereinabove, such as diseases ordisorders associated with androgen receptor activity or in whichandrogen receptor activity is implicated. It is to be understood thatsuch combination therapy constitutes a further aspect of thecompositions and methods of treatment provided herein.

In certain embodiments, a pharmaceutical composition containing one ormore compounds provided herein is formulated as a prodrug. In certainembodiments, prodrugs are useful because they are easier to administerthan the corresponding active form. For example, in certain instances, aprodrug may be more bioavailable (e.g., through oral administration)than is the corresponding active form. In certain instances, a prodrugmay have improved solubility compared to the corresponding active form.In certain embodiments, a prodrug is an ester. In certain embodiments,such prodrugs are less water soluble than the corresponding active form.In certain instances, such prodrugs possess superior transmittal acrosscell membranes, where water solubility is detrimental to mobility. Incertain embodiments, the ester in such prodrugs is metabolicallyhydrolyzed to carboxylic acid. In certain instances the carboxylic acidcontaining compound is the corresponding active form. In certainembodiments, a prodrug contains a short peptide (polyaminoacid) bound toan acid group. In certain of such embodiments, the peptide ismetabolized to form the corresponding active form.

In certain embodiments, a pharmaceutical composition containing one ormore compounds provided herein is useful for treating a conditions ordisorder in a mammalian, and particularly in a human patient. Suitableadministration routes include, but are not limited to, oral, rectal,transmucosal, intestinal, enteral, topical, suppository, throughinhalation, intrathecal, intraventricular, intraperitoneal, intranasal,intraocular and parenteral (e.g., intravenous, intramuscular,intramedullary, and subcutaneous). In certain embodiments,pharmaceutical compositions are administered to achieve local ratherthan systemic exposures. For example, pharmaceutical compositions may beinjected directly in the area of desired effect (e.g., in the renal orcardiac area). In certain embodiments in which the pharmaceuticalcomposition is administered locally, the dosage regimen is adjusted toachieve a desired local concentration of a compound provided herein.

In certain embodiments, a pharmaceutical composition containing one ormore compounds provided herein is administered in the form of a dosageunit (e.g., tablet, capsule, bolus, etc.). In certain embodiments, suchdosage units contain a selective androgen receptor modulator in a dosefrom about 1 μg/kg of body weight to about 50 mg/kg of body weight. Incertain embodiments, such dosage units contain a selective androgenreceptor modulator in a dose from about 2 μg/kg of body weight to about25 mg/kg of body weight. In certain embodiments, such dosage unitscontain a selective androgen receptor modulator in a dose from about 10μg/kg of body weight to about 5 mg/kg of body weight. In certainembodiments, pharmaceutical compositions are administered as needed,once per day, twice per day, three times per day, or four or more timesper day. It is recognized by those skilled in the art that theparticular dose, frequency, and duration of administration depends on anumber of factors, including, without limitation, the biologicalactivity desired, the condition of the patient, and tolerance for thepharmaceutical composition.

In certain embodiments, a pharmaceutical composition provided herein isadministered for a period of continuous therapy. For example, apharmaceutical composition provided herein may be administered over aperiod of days, weeks, months, or years.

Dosage amount, interval between doses, and duration of treatment may beadjusted to achieve a desired effect. In certain embodiments, dosageamount and interval between doses are adjusted to maintain a desiredconcentration of compound in a patient. For example, in certainembodiments, dosage amount and interval between doses are adjusted toprovide plasma concentration of a compound provided herein at an amountsufficient to achieve a desired effect. In certain of such embodimentsthe plasma concentration is maintained above the minimal effectiveconcentration (MEC). In certain embodiments, pharmaceutical compositionsprovided herein are administered with a dosage regimen designed tomaintain a concentration above the MEC for 10-90% of the time, between30-90% of the time, or between 50-90% of the time.

1. Compositions for Oral Administration

In certain embodiments, oral pharmaceutical dosage forms are eithersolid, gel or liquid. The solid dosage forms are tablets, capsules,granules, and bulk powders. Types of oral tablets include compressed,chewable lozenges and tablets which can be enteric-coated, sugar-coatedor film-coated. Capsules can be hard or soft gelatin capsules, whilegranules and powders can be provided in non-effervescent or effervescentform with the combination of other ingredients known to those skilled inthe art.

In certain embodiments, the formulations are solid dosage forms,preferably capsules or tablets. The tablets, pills, capsules, trochesand the like can contain any of the following ingredients, or compoundsof a similar nature: a binder; a diluent; a disintegrating agent; alubricant; a glidant; a sweetening agent; and a flavoring agent.

In certain embodiments, pharmaceutical compositions for oraladministration are push fit capsules made of gelatin. Certain of suchpush fit capsules contain one or more compounds provided herein inadmixture with one or more filler such as lactose, binders such asstarches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In certain embodiments, pharmaceuticalcompositions for oral administration are soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. In certain softcapsules, one or more compounds provided are to be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.

In certain embodiments, pharmaceutical compositions are prepared forbuccal administration. Certain of such pharmaceutical compositions aretablets or lozenges formulated in conventional manner.

Examples of binders for use in the compositions provided herein includemicrocrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, sucrose and starch paste. Lubricants includetalc, starch, magnesium or calcium stearate, lycopodium and stearicacid. Diluents include, for example, lactose, sucrose, starch, kaolin,salt, mannitol and dicalcium phosphate. Glidants include, but are notlimited to, colloidal silicon dioxide. Disintegrating agents includecrosscarmellose sodium, sodium starch glycolate, alginic acid, sodiumalginate, corn starch, potato starch, bentonite, methylcellulose, agarand carboxymethylcellulose. Coloring agents include, for example, any ofthe approved certified water soluble FD and C dyes, mixtures thereof;and water insoluble FD and C dyes suspended on alumina hydrate.Sweetening agents include sucrose, lactose, mannitol and artificialsweetening agents such as saccharin, and any number of spray driedflavors. Flavoring agents include natural flavors extracted from plantssuch as fruits and synthetic blends of compounds which produce apleasant sensation, such as, but not limited to peppermint and methylsalicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emetic-coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition can also be formulated incombination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup can contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. The activeingredient is a compound or pharmaceutically acceptable derivativethereof as described herein. Higher concentrations, up to about 98% byweight of the active ingredient can be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric-coated tablets, because of theenteric-coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar-coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film-coated tablets are compressedtablets which have been coated with a polymer or other suitable coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents can also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar-coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and can contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicacid, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas saccharin. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Organic acids include citric and tartaric acid. Sources ofcarbon dioxide include sodium bicarbonate and sodium carbonate. Coloringagents include any of the approved certified water soluble FD and Cdyes, and mixtures thereof. Flavoring agents include natural flavorsextracted from plants such fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, can be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations can be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603. Briefly, such formulations include, but are not limited to,those containing a compound provided herein, a dialkylated mono- orpoly-alkylene glycol, including, but not limited to,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer tothe approximate average molecular weight of the polyethylene glycol, andone or more antioxidants, such as butylated hydroxytoluene (BHT),butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, thiodipropionic acid and its esters,and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl)acetals of lower alkyl aldehydes such as acetaldehydediethyl acetal.

In all embodiments, tablets and capsules formulations can be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they can becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

Exemplary compositions can include fast-dissolving diluents such asmannitol, lactose, sucrose, and/or cyclodextrins. Also included in suchformulations can be high molecular weight excipients such as celluloses(AVICEL®) or polyethylene glycols (PEG); an excipient to aid mucosaladhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleicanhydride copolymer (e.g., GANTREZ®); and agents to control release suchas polyacrylic copolymer (e.g., CARBOPOL 934®). Lubricants, glidants,flavors, coloring agents and stabilizers can also be added for ease offabrication and use.

In certain of such embodiments, a pharmaceutical composition for oraladministration is formulated by combining one or more compounds providedherein with one or more pharmaceutically acceptable carriers. Certain ofsuch carriers enable compounds provided herein to be formulated astablets, pills, dragees, capsules, liquids, gels, syrups, slurries,suspensions and the like, for oral ingestion by a patient. In certainembodiments, pharmaceutical compositions for oral use are obtained bymixing one or more compounds provided herein and one or more solidexcipient. Suitable excipients include, but are not limited to, fillers,such as sugars, including lactose, sucrose, mannitol, or sorbitol;cellulose preparations such as, for example, maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). In certain embodiments, such a mixture isoptionally ground and auxiliaries are optionally added. In certainembodiments, pharmaceutical compositions are formed to obtain tablets ordragee cores. In certain embodiments, disintegrating agents (e.g., crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof,such as sodium alginate) are added.

In certain embodiments, dragee cores are provided with coatings. Incertain of such embodiments, concentrated sugar solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquersolutions, and suitable organic solvents or solvent mixtures. Dyestuffsor pigments may be added to tablets or dragee coatings.

In certain embodiments, a daily dosage regimen for a patient contains anoral dose of between 0.1 mg and 2000 mg of a compound provided herein.In certain embodiments, a daily dosage regimen is administered as asingle daily dose. In certain embodiments, a daily dosage regimen isadministered as two, three, four, or more than four doses.

2. Injectables, Solutions and Emulsions

In certain embodiments, the pharmaceutical composition is prepared fortransmucosal administration. In certain of such embodiments penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art.

Parenteral administration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously is also contemplatedherein. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol,mannitol, 1,3-butanediol, Ringer's solution, an isotonic sodium chloridesolution or ethanol. In addition, if desired, the pharmaceuticalcompositions to be administered can also contain minor amounts ofnon-toxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents, stabilizers, solubility enhancers, and other suchagents, such as for example, mono- or diglycerides, fatty acids, such asoleic acid, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins. Implantation of a slow-release or sustained-releasesystem, such that a constant level of dosage is maintained (see, e.g.,U.S. Pat. No. 3,710,795) is also contemplated herein. Briefly, acompound provided herein is dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions can be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the active compound to the treatedtissue(s). The active ingredient can be administered at once, or can bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and can bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values can also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice offormulations provided herein.

The compounds can be formulated in any suitable vehicle or form. Forexample, they can be in micronized or other suitable form and/or can bederivatized to produce a more soluble active product or to produce aprodrug or for other purposes. The form of the resulting mixture dependsupon a number of factors, including, for example, an intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the condition and can be empiricallydetermined.

In certain embodiments, a pharmaceutical composition is prepared foradministration by injection wherein the pharmaceutical compositioncontains a carrier and is formulated in aqueous solution, such as wateror physiologically compatible buffers such as Hanks's solution, Ringer'ssolution, or physiological saline buffer. In certain embodiments, otheringredients are included (e.g., ingredients that aid in solubility orserve as preservatives). In certain embodiments, injectable suspensionsare prepared using appropriate liquid carriers, suspending agents andthe like. Certain pharmaceutical compositions for injection arepresented in unit dosage form, e.g., in ampules or in multi dosecontainers.

Certain pharmaceutical compositions for injection are suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Certain solvents suitable for use in pharmaceutical compositionsfor injection include, but are not limited to, lipophilic solvents andfatty oils, such as sesame oil, synthetic fatty acid esters, such asethyl oleate or triglycerides, and liposomes. Aqueous injectionsuspensions may contain substances that increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, such suspensions may also contain suitablestabilizers or agents that increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.

In certain embodiments, the pharmaceutical composition is prepared foradministration by inhalation. Certain of such pharmaceuticalcompositions for inhalation are prepared in the form of an aerosol sprayin a pressurized pack or a nebulizer. Certain of such pharmaceuticalcompositions contain a propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In certain embodiments using a pressurized aerosol,the dosage unit may be determined with a valve that delivers a meteredamount. In certain embodiments, capsules and cartridges for use in aninhaler or insufflator may be formulated. Certain of such formulationscontain a powder mixture of a compound provided herein and a suitablepowder base such as lactose or starch.

In certain embodiments, the pharmaceutical compositions provided areadministered by continuous intravenous infusion. In certain of suchembodiments, from 0.1 mg to 500 mg of the composition is administeredper day.

3. Lyophilized Powders

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They can also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, ina suitable solvent. The solvent can contain an excipient which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that can beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose or other suitable agent. Thesolvent can also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art at,typically, about neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. Generally,the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage 10-1000 mg, inone embodiment, 100-500 mg or multiple dosages of the compound. Thelyophilized powder can be stored under appropriate conditions, such asat about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, about 1-50 mg, preferably 5-35 mg, more preferably about9-30 mg of lyophilized powder, is added per mL of sterile water or othersuitable carrier. The precise amount depends upon the selected compound.Such amount can be empirically determined.

4. Topical Administration

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture can be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof can beformulated as aerosols for topical application, such as by inhalation(see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, whichdescribe aerosols for delivery of a steroid useful for treatment ofinflammatory diseases, particularly asthma). These formulations foradministration to the respiratory tract can be in the form of an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the formulation will typically have diameters ofless than 50 microns, preferably less than 10 microns.

In certain embodiments, the pharmaceutical compositions for inhalationare prepared in the form of an aerosol spray in a pressurized pack or anebulizer. Certain of such pharmaceutical compositions contain apropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Incertain embodiments using a pressurized aerosol, the dosage unit can bedetermined with a valve that delivers a metered amount. In certainembodiments, capsules and cartridges for use in an inhaler orinsufflator can be formulated. Certain of such formulations contain apowder mixture of a compound provided herein and a suitable powder basesuch as lactose or starch.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which can contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

The compounds can be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered. Thesesolutions, particularly those intended for ophthalmic use, can beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts. In certain embodiments in which the compositions isadministered locally, the dosage regimen is adjusted to achieve adesired local concentration of a compound provided herein.

In certain embodiments, the pharmaceutical composition is prepared fortopical administration. Certain of such pharmaceutical compositionscontain bland moisturizing bases, such as ointments or creams. Exemplarysuitable ointment bases include, but are not limited to, petrolatum,petrolatum plus volatile silicones, lanolin and water in oil emulsionssuch as Eucerin™, available from Beiersdorf (Cincinnati, Ohio).Exemplary suitable cream bases include, but are not limited to, Nivea™Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP),Purpose Cream™, available from Johnson & Johnson (New Brunswick, N.J.),hydrophilic ointment (USP) and Lubriderm™, available from Pfizer (MorrisPlains, N.J.).

In certain embodiments, the formulation, route of administration anddosage for the pharmaceutical composition provided herein can be chosenin view of a particular patient's condition. (See e.g., Fingl et al.1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1 p. 1). Incertain embodiments, the pharmaceutical composition is administered as asingle dose. In certain embodiments, a pharmaceutical composition isadministered as a series of two or more doses administered over one ormore days.

5. Compositions for Other Routes of Administration

Other routes of administration, such as topical application, transdermalpatches, and rectal administration are also contemplated herein.

In certain embodiments, the pharmaceutical composition is prepared fortopical administration such as rectal administration. The pharmaceuticaldosage forms for rectal administration include, but are not limited torectal suppositories, capsules and tablets for systemic effect. Incertain embodiments, a pharmaceutical agent is prepared for rectaladministration, such as a suppositories or retention enema. Certain ofsuch pharmaceutical agents contain known ingredients, such as cocoabutter and/or other glycerides. Rectal suppositories are used hereinmean solid bodies for insertion into the rectum which melt or soften atbody temperature releasing one or more pharmacologically ortherapeutically active ingredients. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethyleneglycol) and appropriate mixtures of mono-, di- and triglycerides offatty acids. Combinations of the various bases can be used. In certainembodiments, the pharmaceutical compositions contain bland moisturizingbases, such as ointments or creams. Exemplary suitable ointment basesinclude, but are not limited to, petrolatum, petrolatum plus volatilesilicones, lanolin and water in oil emulsions such as Eucerin™,available from Beiersdorf (Cincinnati, Ohio). Exemplary suitable creambases include, but are not limited to, Nivea™ Cream, available fromBeiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose Cream™,available from Johnson & Johnson (New Brunswick, N.J.), hydrophilicointment (USP) and Lubriderm™, available from Pfizer (Morris Plains,N.J.). Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories can be prepared either by thecompressed method or by molding. The typical weight of a rectalsuppository is about 2 to 3 gm.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

6. Articles of Manufacture

The compounds or pharmaceutically acceptable derivatives can be packagedas articles of manufacture containing packaging material, within thepackaging material a compound or pharmaceutically acceptable derivativethereof provided herein, which is effective for modulating the activityof androgen receptor, or for treatment, prevention or amelioration ofone or more symptoms of androgen receptor mediated diseases ordisorders, or diseases or disorders in which androgen receptor activityis implicated, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable derivative thereof, is usedfor modulating the activity of androgen receptor or for treatment,prevention or amelioration of one or more symptoms of androgen receptormediated diseases or disorders, or diseases or disorders in whichandrogen receptor activity is implicated.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment. A wide array of formulations ofthe compounds and compositions provided herein are contemplated as are avariety of treatments for any disease or disorder in which androgenreceptor activity is implicated as a mediator or contributor to thesymptoms or cause.

In certain embodiments, the pharmaceutical compositions can be presentedin a pack or dispenser device which can contain one or more unit dosageforms containing a compound provided herein. The pack can for examplecontain metal or plastic foil, such as a blister pack. The pack ordispenser device can be accompanied by instructions for administration.The pack or dispenser can also be accompanied with a notice associatedwith the container in form prescribed by a governmental agencyregulating the manufacture, use, or sale of pharmaceuticals, whichnotice is reflective of approval by the agency of the form of the drugfor human or veterinary administration. Such notice, for example, can bethe labeling approved by the U.S. Food and Drug Administration forprescription drugs, or the approved product insert. Compositionscontaining a compound provided herein formulated in a compatiblepharmaceutical carrier can also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition.

E. Evaluation of the Activity of the Compounds

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds provided herein to identify thosethat possess activity as androgen receptor modulators. In vitro and invivo assays known in the art can be used to evaluate the activity of thecompounds provided herein as androgen receptor modulators. Exemplaryassays include, but are not limited to fluorescence polarization assay,luciferase assay, co-transfaction assay. In certain embodiments, thecompounds provided herein are capable of modulating activity of androgenreceptor in a “co-transfection” assay (also called a “cis-trans” assay),which is known in the art. See e.g., Evans et al., Science, 240:889-95(1988); U.S. Pat. Nos. 4,981,784 and 5,071,773; Pathirana et al.,“Nonsteroidal Human Progesterone Receptor Modulators from the Marie AlgaCymopolia Barbata,” Mol. Pharm. 47:630-35 (1995)). Modulating activityin a co-transfection assay has been shown to correlate with in vivomodulating activity. Thus, in certain embodiments, such assays arepredictive of in vivo activity. See, e.g, Berger et al., J. SteroidBiochem. Molec. Biol. 41:773 (1992).

In certain co-transfection assays, two different co-transfectionplasmids are prepared. In the first co-transfection plasmid, cloned cDNAencoding an intracellular receptor (e.g., androgen receptor) isoperatively linked to a constitutive promoter (e.g., the SV 40promoter). In the second co-transfection plasmid, cDNA encoding areporter protein, such as firefly luciferase (LUC), is operativelylinked to a promoter that is activated by a receptor-dependantactivation factor. Both co-transfection plasmids are co-transfected intothe same cells. Expression of the first co-transfection plasmid resultsin production of the intracellular receptor protein. Activation of thatintracellular receptor protein (e.g., by binding of an agonist) resultsin production of a receptor-dependant activation factor for the promoterof the second co-transfection plasmid. That receptor-dependantactivation factor in turn results in expression of the reporter proteinencoded on the second co-transfection plasmid. Thus, reporter proteinexpression is linked to activation of the receptor. Typically, thatreporter activity can be conveniently measured (e.g., as increasedluciferase production).

Certain co-transfection assays can be used to identify agonists, partialagonists, and/or antagonists of intracellular receptors. In certainembodiments, to identify agonists, co-transfected cells are exposed to atest compound. If the test compound is an agonist or partial agonist,reporter activity is expected to increase compared to co-transfectedcells in the absence of the test compound. In certain embodiments, toidentify antagonists, the cells are exposed to a known agonist (e.g.,androgen for the androgen receptor) in the presence and absence of atest compound. If the test compound is an antagonist, reporter activityis expected to decrease relative to that of cells exposed only to theknown agonist.

In certain embodiments, compounds provided herein are used to detect thepresence, quantity and/or state of receptors in a sample. In certain ofsuch embodiments, samples are obtained from a patient. In certainembodiments, compounds are radio- or isotopically-labeled. For example,compounds provided herein that selectively bind androgen receptors maybe used to determine the presence of such receptors in a sample, such ascell homogenates and lysates.

F. Methods of Use of the Compounds and Compositions

Methods of use of the compounds and compositions provided herein alsoare provided. The methods include in vitro and in vivo uses of thecompounds and compositions for altering androgen receptor activity andfor treatment, prevention, or amelioration of one or more symptoms ofdiseases or disorder that are modulated by androgen receptor activity,or in which androgen receptor activity, is implicated. In certainembodiments, provided herein are methods of treating a patient byadministering a compound provided herein. In certain embodiments, suchpatient exhibits symptoms or signs of a androgen receptor mediatedcondition. In certain embodiments, a patient is treated prophylacticallyto reduce or prevent the occurrence of a condition.

The compounds provided herein can be used in the treatment of a varietyof conditions including, but not limited to, maintenance of musclestrength and function (e.g., in the elderly); reversal or prevention offrailty or age-related functional decline (“ARFD”) in the elderly (e.g.,sarcopenia); treatment of catabolic side effects of glucocorticoids;prevention and/or treatment of reduced bone mass, density or growth(e.g., osteoporosis and osteopenia); treatment of chronic fatiguesyndrome (CFS); chronic myalgia; treatment of acute fatigue syndrome andmuscle loss following elective surgery (e.g., post-surgicalrehabilitation); accelerating of wound healing; accelerating bonefracture repair (such as accelerating the recovery of hip fracturepatients); accelerating healing of complicated fractures, e.g.distraction osteogenesis; in joint replacement; prevention ofpost-surgical adhesion formation; acceleration of tooth repair orgrowth; maintenance of sensory function (e.g., hearing, sight,olefaction and taste); treatment of periodontal disease; treatment ofwasting secondary to fractures and wasting in connection with chronicobstructive pulmonary disease (COPD), chronic liver disease, AIDS,weightlessness, cancer cachexia, burn and trauma recovery, chroniccatabolic state (e.g., coma), eating disorders (e.g., anorexia) andchemotherapy; treatment of cardiomyopathy; treatment ofthrombocytopenia; treatment of growth retardation in connection withCrohn's disease; treatment of short bowel syndrome; treatment ofirritable bowel syndrome; treatment of inflammatory bowel disease;treatment of Crohn's disease and ulcerative colits; treatment ofcomplications associated with transplantation; treatment ofphysiological short stature including growth hormone deficient childrenand short stature associated with chronic illness; treatment of obesityand growth retardation associated with obesity; treatment of anorexia(e.g., associated with cachexia or aging); treatment of hypercortisolismand Cushing's syndrome; Paget's disease; treatment of osteoarthritis;induction of pulsatile growth hormone release; treatment ofosteochondrodysplasias; treatment of depression, nervousness,irritability and stress; treatment of reduced mental energy and lowself-esteem (e.g., motivation/assertiveness); improvement of cognitivefunction (e.g., the treatment of dementia, including Alzheimer's diseaseand short term memory loss); treatment of catabolism in connection withpulmonary dysfunction and ventilator dependency; treatment of cardiacdysfunction (e.g., associated with valvular disease, myocardialinfarction, cardiac hypertrophy or congestive heart failure); loweringblood pressure; protection against ventricular dysfunction or preventionof reperfusion events; treatment of adults in chronic dialysis; reversalor slowing of the catabolic state of aging; attenuation or reversal ofprotein catabolic responses following trauma (e.g., reversal of thecatabolic state associated with surgery, congestive heart failure,cardiac myopathy, burns, cancer, COPD etc.); reducing cachexia andprotein loss due to chronic illness such as cancer or AIDS; treatment ofhyperinsulinemia including nesidioblastosis; treatment ofimmunosuppressed patients; treatment of wasting in connection withmultiple sclerosis or other neurodegenerative disorders; promotion ofmyelin repair; maintenance of skin thickness; treatment of metabolichomeostasis and renal homeostasis (e.g., in the frail elderly);stimulation of osteoblasts, bone remodeling and cartilage growth;regulation of food intake; treatment of insulin resistance, includingNIDDM, in mammals (e.g., humans); treatment of insulin resistance in theheart; improvement of sleep quality and correction of the relativehyposomatotropism of senescence due to high increase in REM sleep and adecrease in REM latency; treatment of hypothermia; treatment ofcongestive heart failure; treatment of lipodystrophy (e.g., in patientstaking HIV or AIDS therapies such as protease inhibitors); treatment ofmuscular atrophy (e.g., due to physical inactivity, bed rest or reducedweight-bearing conditions); treatment of musculoskeletal impairment(e.g., in the elderly); improvement of the overall pulmonary function;treatment of sleep disorders; and the treatment of the catabolic stateof prolonged critical illness; treatment of hirsutism, acne, seborrhea,androgenic alopecia, anemia, hyperpilosity, benign prostate hypertrophy,adenomas and neoplasies of the prostate (e.g., advanced metastaticprostate cancer) and malignant tumor cells containing the androgenreceptor, such as is the case for breast, brain, skin, ovarian, bladder,lymphatic, liver and kidney cancers; cancers of the skin, pancreas,endometrium, lung and colon; osteosarcoma; hypercalcemia of malignancy;metastatic bone disease; treatment of spermatogenesis, endometriosis andpolycystic ovary syndrome; conteracting preeclampsia, eclampsia ofpregnancy and preterm labor; treatment of premenstural syndrome;treatment of vaginal dryness; age related decreased testosterone levelsin men, male menopause, hypogonadism, male hormone replacement, male andfemale sexual dysfunction (e.g., erectile dysfunction, decreased sexdrive, sexual well-being, decreased libido), male and femalecontraception, hair loss, Reaven's Syndrome and the enhancement of boneand muscle performance/strength. The term treatment is also intended toinclude prophylactic treatment.

In certain embodiments, the compounds provided herein are used to treatacne, male-pattern baldness, wasting diseases, hirsutism, hypogonadism,osteoporoses, infertility, impotence, obesity, and cancer. In certainembodiments, one or more compounds provided herein are used to stimulatehematopoiesis. In certain embodiments, one or more compounds providedherein are used for contraception.

In certain embodiments, one or more compounds provided herein are usedto treat cancer. Certain exemplary cancers include, but are not limitedto, breast cancer, colorectal cancer, gastric carcinoma, glioma, headand neck squamous cell carcinoma, papillary renal carcinoma, leukemia,lymphoma, Li-Fraumeni syndrome, malignant pleural mesothelioma,melanoma, multiple myeloma, non-small cell lung cancer, synovialsarcoma, thyroid carcinoma, transitional cell carcinoma of urinarybladder, and prostate cancer, including, but not limited to prostatichyperplasia.

In certain embodiments, one or more compounds provided herein are usedto improve athletic performance. In certain such embodiments, one ormore compounds provided herein are used, for example to shorten the timenormally needed to recover from physical exertion or to increase musclestrength. Athletes to whom one or more compounds provided herein can beadministered include, but are not limited to, horses, dogs, and humans.In certain embodiments, one or more compounds provided herein areadministered to an athlete engaged in a professional or recreationalcompetition, including, but not limited to weight-lifting,body-building, track and field events, and any of various team sports.In certain embodiments, provided are methods for treating a patient byadministering one or more selective androgen receptor agonists and/orpartial agonists. Exemplary conditions that can be treated with suchselective androgen receptor agonists and/or partial agonist include, butare not limited to, hypogonadism, wasting diseases, cancer cachexia,frailty, infertility, and osteoporosis. In certain embodiments, aselective androgen receptor agonist or partial agonist is used for malehormone replacement therapy. In certain embodiments, one or moreselective androgen receptor agonists and/or partial agonists are used tostimulate hematopoiesis. In certain embodiments, a selective androgenreceptor agonist or partial agonist is used as an anabolic agent. Incertain embodiments, a selective androgen receptor agonist and/orpartial agonist is used to improve athletic performance.

In certain embodiments, provided herein are methods for treating apatient by administering one or more selective androgen receptorantagonists and/or partial agonists. Exemplary conditions that may betreated with such one or more selective androgen receptor antagonistsand/or partial agonists include, but are not limited to, hirsutism,acne, male-pattern baldness, prostatic hyperplasia, and cancer,including, but not limited to, various hormone-dependent cancers,including, without limitation, prostate and breast cancer.

G. Combination Therapies

In certain embodiments, one or more compounds or compositions providedherein can be co-administered with one or more other pharmaceuticalagents. In certain embodiments, such one or more other pharmaceuticalagents are designed to treat the same disease or condition as the one ormore compounds or pharmaceutical compositions provided herein. Incertain embodiments, such one or more other pharmaceutical agents aredesigned to treat a different disease or condition as the one or morecompounds or compositions provided herein. In certain embodiments, suchone or more other pharmaceutical agents are designed to treat anundesired effect of one or more compounds or compositions providedherein. In certain embodiments, one or more compounds or compositionsprovided herein is co-administered with another pharmaceutical agent totreat an undesired effect of that other pharmaceutical agent.

In certain embodiments, compounds or compositions provided herein andone or more other pharmaceutical agents are administered at the sametime. In certain embodiments, compounds or compositions provided hereinand one or more other pharmaceutical agents are administered at thedifferent times. In certain embodiments, compounds or compositionsprovided herein and one or more other pharmaceutical agents are preparedtogether in a single formulation. In certain embodiments, compounds orcompositions provided herein and one or more other pharmaceutical agentsare prepared separately.

Examples of pharmaceutical agents that may be co-administered withcompounds or compositions provided herein include, but are not limitedto, analgesics (e.g., acetaminophen); anti-inflammatory agents,including, but not limited to non-steroidal anti-inflammatory drugs(e.g., ibuprofen, COX-1 inhibitors, and COX-2, inhibitors); salicylates;antibiotics; antivirals; antifungal agents; antidiabetic agents (e.g.,biguanides, glucosidase inhibitors, insulins, sulfonylureas, andthiazolidenediones); adrenergic modifiers; diuretics; hormones (e.g.,anabolic steroids, androgen, estrogen, calcitonin, progestin,somatostan, and thyroid hormones); immunomodulators; muscle relaxants;antihistamines; osteoporosis agents (e.g., biphosphonates, calcitonin,and estrogens); prostaglandins, antineoplastic agents; psychotherapeuticagents; sedatives; poison oak or poison sumac products; antibodies; andvaccines.

In other embodiments, pharmaceutical agents that may be co-administeredwith compounds or compositions provided herein include, but are notlimited to, other modulators of nuclear hormone receptors or othersuitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-diabetic agents;anti-osteoporosis agents; anti-obesity agents; anti-inflammatory agents;anti-anxiety agents; anti-depressants; anti-hypertensive agents;anti-platelet agents; anti-thrombotic and thrombolytic agents; cardiacglycosides; cholesterol/lipid lowering agents; mineralocorticoidreceptor antagonists; phosphodiesterase inhibitors; protein tyrosinekinase inhibitors; thyroid mimetics (including thyroid receptoragonists); anabolic agents; HIV or AIDS therapies; therapies used in thetreatment of Alzheimer's and other cognitive disorders; therapies usedin the treatment of sleeping disorders; anti-proliferative agents; andanti-tumor agents.

EXAMPLES

The following examples, including experiments and results achieved, areprovided for illustrative purposes only and are not to be construed aslimiting the claimed subject matter.

Example 1

N,N-bis(2,2,2-trifluoroethyl)-3-methyl-4-nitroaniline (Compound 101,Structure 2 of Scheme I, where R¹═NO₂, R²═CH₃, R³═R⁴═R⁵═R⁶═R⁷═R¹⁰═R¹¹═H,R⁸═R⁹═CF₃)

3-Methyl-4-nitroaniline 3.9 g (25 mmol) was dissolved in 100 mL oftrifluoroacetic acid with stirring under N₂ at 60° C. Next, sodiumborohydride pellets (14 g, 15 eq.) were added portionwise. Ten minutesafter the addition of the pellets, the reaction was heated to 90° C.After 12 h at 90° C., the reaction was cooled, added slowly to water,and then filtered. The resulting solid filtrate was washed first withwater and then with hexanes and was then dried. This procedure resultedin 6.6 g (82% yield) of a light yellow powder. Data for compound 101:¹H-NMR (CDCl₃, 500 MHz) 8.10 (d, 1H, J=9.3 Hz), 6.78 (dd, 1H, J=9.3 and2.9 Hz), 6.72 (d, 1H, J=2.9 Hz), 4.13 (q, 4H, J=8.4 Hz), 2.66 (s, 3H).

Example 2

N,N-bis(2,2,2-trifluoroethyl)-4-nitroaniline (Compound 102, Structure 2of Scheme I, where R¹═NO₂, R²═R³═R⁴═R⁵═R⁶═R⁷═R¹⁰═R¹¹═H, R⁸═R⁹═CF₃)

This compound was prepared using the method described in Example 1,except that 4-nitroaniline was used in place of 3-methyl-4-nitroaniline.Compound 102 was isolated as a solid: ¹H NMR (CDCl₃, 400 MHz) 8.19 (d,2H, J=9.5 Hz), 86.93 (d, 2H, J=9.5 Hz), 4.16 (q, 2H, J=8.3 Hz).

Example 3A

4-Bromo-N,N-bis(2,2,2-trifluoroethyl)-3-(trifluoromethyl)aniline(Compound 103A, Structure 2 of Scheme I, where R¹=bromo,R²=trifluoromethyl; R³═R⁴═R⁵═R⁶═R⁷═R¹⁰═R¹¹═H, R⁸═R⁹═CF₃)

This compound was prepared using the method described in Example 1,except that 4-bromo-3-(trifluoromethyl)aniline was used in place of3-methyl-4-nitroaniline. Compound 103A was isolated as a solid: ¹H NMR(CDCl₃, 400 MHz) 7.58 (d, 1H, J=8.8 Hz), 7.19 (d, 1H, J=3.2 Hz), 6.91(dd, 1H, J=8.8 and 3.2 Hz), 4.06 (q, 4H, J=8.5 Hz).

Example 3

4-(Bis(2,2,2-trifluoroethyl)amino)-2-(trifluoromethyl)benzonitrile(Compound 103, Structure 2 of Scheme I, where R¹=cyano,R²=trifluoromethyl; R³═R⁴═R⁵═R⁶═R⁷═R¹⁰═R¹¹═H, R⁸═R⁹═CF₃)

To prepare this compound, Zn(CN)₂ (26 mg, 0.22 mmol), Pd(PPh₃)₄, andCompound 103A (77 mg, 0.19 mmol) were combined in a dry Schlenk flask.The mixture was then added to 2 mL of a 1% DMF/water solution, which hadbeen degassed by bubbling N₂ for 20 minutes. That mixture was thenheated to 130° C. for 20 h, and then partitioned with EtOAc andsaturated aqueous NH₄Cl. The organic layer washed sequentially withwater and then with brine, dried over MgSO₄, filtered, and concentrated.Flash chromatography (silica gel, 4:1 hexanes:EtOAc) afforded Compound103. Compound 103 was isolated as a solid: ¹H NMR (CDCl₃, 400 MHz) 7.73(d, 1H, J=8.8 Hz), 7.19 (d, 1H, J=2.8 Hz), 7.08 (dd, 1H, J=8.8 and 2.8Hz), 4.16 (q, 4H, J=8.2 Hz).

Example 4

(5R)—N-(4-nitrophenyl)-5-(dimethyl-tert-butylsilyloxymethyl)-2-pyrrolidone(Compound 104, Structure 5 of Scheme II, where R¹=nitro,R¹⁰=dimethyl-tert-butylsilyloxymethyl, R²═R³═R⁴═R⁵═R⁹═R¹²═R¹³═H, R^(6a)and R^(7a) form a carbonyl, n=0, Z=CH₂)

General Procedure 1 (Palladium mediated coupling of aryl bromide andamine or amide): A solution of an aryl bromide (such as4-bromo-nitrobenzene in toluene (0.05-0.2 M), Cs₂CO₃ (2-3 equiv),Pd₂(dba)₃ (1-3 mol %), and (R)—BINAP (2.0 mg, 0.003 mmol, 1.5-4.5 mol %)are combined in a schlenk tube. The amine or amide (3-5 equiv.) is thenadded to the reaction flask. The resulting reaction mixture is heated to100° C. for 4-48 hours, cooled to room temperature, diluted with Et₂O,filtered, and concentrated in vacuo. Chromatography (silica gel,CH₂Cl₂:hexanes or EtOAc:hexanes) of the crude mixture afforded compoundsof Structure 5.

Compound 104 was prepared according the General Procedure 1 using4-bromonitrobenzene as the aryl bromide. Compound 104 was isolated as ayellow oil. ¹H NMR (CDCl₃, 400 MHz) 8.1 (s, 1H), 8.0 (m, 2H), 4.5 (m,1H), 3.76 (dd, 1H, J=3.9 and 10.7 Hz), 3.70 (dd, 1H, J=3.4 and 10.7 Hz),2.8 (m, 1H), 2.6 (m, 1H), 2.4 (m, 1H), 2.2 (m, 1H), 0.8 (s, 9H), 0.1 (s,3H), 0.0 (s, 3H).

Example 5

(5R)—N-(4-nitrophenyl)-5-(hydroxymethyl)-2-pyrrolidone (Compound 105,Structure 5 of Scheme II, where R¹=nitro, R¹⁰=hydroxymethyl, R²═R³═R⁴═R⁵═R⁹═R¹²═R¹³═H, R^(6a) and R^(7a) form a carbonyl, n=0, Z=CH₂)

Compound 105 was prepared by hydrolyzing the silyl group of Compound104. Compound 105 was isolated as an oil: ¹H NMR (CDCl₃, 400 MHz) 8.25(d, 2H, J=9.3 Hz), 7.77 (d, 2H, J=9.3 Hz), 4.48 (ddt, 1H, J=8.6, 4.6 and3.0 Hz), 3.82 (dt, 1H, J=11.4 and 4.6 Hz), 3.74 (ddd, 1H, J=11.4, 5.5and 3.0 Hz), 2.81 (ddd, 1H, J=17.5, 10.0 and 8.6 Hz), 2.58 (ddd, 1H,J=17.5, 10.1 and 4.3 Hz), 2.36 (ddt, 1H, J=13.0, 10.1 and 8.6 Hz), 2.22(dddd, 1H, J=13.0, 10.0, 4.3 and 3.0 Hz), 1.61 (dd, 1H, J=5.5 and 4.6Hz).

Example 6

(2R)—N-(4-nitro-3-trifluoromethylphenyl)-2-(dimethyl-tert-butylsilyloxymethyl)pyrrolidine(Compound 106, Structure 5 of Scheme II, where R¹=nitro,R²=trifluoromethyl, R¹⁰=dimethyl-tert-butylsilyloxymethyl,R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂)

To prepare this compound, first(5R)—N-(4-nitro-3-trifluoromethylphenyl)-2-(dimethyl-tert-butylsilyloxymethyl)-2-pyrrolidone(Compound 107, Structure 5 of Scheme II, where R¹=nitro,R²=trifluoromethyl, R¹⁰=dimethyl-tert-butylsilyloxymethyl,R³═R⁴═R⁵═R⁹═R¹²═R¹³═H, R^(6a) and R^(7a) form a carbonyl, n=0, Z=CH₂)was prepared using the method described in Example 4, except that3-trifluoromethyl-4-nitrobromobenzene was used in place of4-nitrobromobenzene. Compound 107 (1.94 g, 4.6 mmol) was then dissolvedin 3 mL of dry THF with stirring and then cooled in an ice water bath.An alane/N,N-dimethylethylamine complex (36 mL, 18 mmol) was added andthe mixture was allowed to warm to room temperature. After 1 hour, 50 mLof methanol and 4 mL of glacial acetic acid were added, followed by theaddition of sodium cyanoborohydride (2.89 g, 46 mmol). After 10 minutes,the reaction mixture was concentrated under reduced pressure. Water wasadded and the solution was extracted with EtOAc. The extracted organiclayer washed with saturated NaHCO₃ and brine (2 times), dried (MgSO₄)and concentrated under reduced pressure. Chromatography (silica, 50%EtOAc:Hex) afforded 624 mg (41% yield) of a yellow oil. Data forCompound 106: ¹H NMR (CDCl₃, 400 MHz) 8.10 (d, 1H, J=9.27), 6.99 (d, 1H,J=2.44 Hz), 6.72 (dd, 1H, J=2.93 and 9.27 Hz), 4.05 (m, 1H), 3.70 (dd,1H, J=4.88 and 10.25 Hz), 3.63 (dd, 1H, J=6.34 and 10.25 Hz), 3.55 (m,1H(, 3.35 (m, 1H), 2.0-2.2 (m, 4H), 0.9 (s, 9H), 0.05 (s, 3H), 0.04 (s,3H). LCMS 404 (M⁺), 259 (M⁺-CH₂OTBS, 100%).

Example 7

(2R)—N-(4-nitro-3-trifluoromethylphenyl)-2-(hydroxymethyl)pyrrolidine(Compound 108, Structure 5 of Scheme II, where R¹=nitro,R²=trifluoromethyl, R¹⁰=hydroxymethyl,R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂)

Compound 106 from Example 6 (620 mg, 1.53 mmol) was dissolved in 4 mL ofethanol with stirring and 1 mL of concentrated HCl was added at roomtemperature. After the reaction was judged complete by TLC (40%EtOAc/hexanes) the pH was adjusted to approximately pH 8 using 1N NaOH.The mixture was extracted with EtOAc and the organic layer washed withbrine, dried (MgSO₄) and concentrated under reduced pressure. Theresulting oil was triturated with hexanes, decanted and dried to afforda yellow oil (354 mg, 79% yield-). Data for Compound 108: ¹H NMR (CDCl₃,400 MHz) 8.08 (d, 1H, J=9.27 Hz), 7.0 (d, 1H, J=2.44 Hz), 6.77 (dd, 1H,J=2.44 and 9.27 Hz), 4.09 (m, 1H), 3.77 (m, 1H), 3.71 (m, 1H), 3.62 (m,1H), 3.36 (m, 1H), 2.1-2.2 (m, 4H), and 1.63 (m, 1H).

Example 8

(2R)—N-(4-nitrophenyl)-2-(hydroxymethyl)pyrrolidine (Compound 109,Structure 5 of Scheme II, where R¹=nitro, R¹⁰=hydroxymethyl,R²═R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂)

This compound was prepared by reduction of the carbonyl group ofCompound 105 using the same reaction described in Example 6. Data forCompound 109: ¹H NMR (CDCl₃, 400 MHz) 8.16 (m, 2H), 6.65 (m, 2H), 4.06(m, 1H), 3.78 (m, 1H), 3.68 (m, 1H), 3.59 (m, 1H), 3.35 (m, 1H), 2.1-2.2(m, 4H), 1.6 (m, 1H).

Example 9

(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine (Compound110, Structure 5 of Scheme II, where R¹=nitro, R²=trifluoromethyl,R¹⁰=formyl, R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂)

This compound was prepared by oxidation of Compound 108 from Example 7.Data for Compound 110: ¹H NMR (CDCl₃, 400 MHz) 9.63 (d, 1H, J=2.44 Hz),8.08 (d, 1H, J=9.27 Hz), 6.89 (d, 1H, J=2.44 Hz), 6.65 (dd, 1H, J=2.44and 9.27 Hz), 4.38 (m, 1H), 3.75 (m, 1H), 3.56 (m, 1H), 2.37 (m, 2H),2.23 (m, 1H), 2.1 (m, 1H).

Example 10

(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(Compound III, Structure 5 of Scheme II, where R¹=nitro,R²=trifluoromethyl, R¹⁰=1-(S)-hydroxy-2,2,2-trifluoroethyl,R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂) and(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(Compound 112, Structure 5 of Scheme II, where R¹=nitro,R²=trifluoromethyl, R¹⁰=1-(R)-hydroxy-2, 2,2-trifluoroethyl,R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂)

To prepare these compounds, compound 110 from Example 9 (290 mg, 1.01mmol) was dissolved in 8 mL of dry THF and cooled in an dryice/isopropanol/acetone bath with stirring. Cesium fluoride (760 mg, 5mmol) and TMSCF₃ (163 μL, 1.1 mmol) were added and the reaction wasallowed to warm to room temperature. After 12 hours, water was added andthe mixture was extracted into EtOAc, dried (MgSO₄) and concentratedunder reduced pressure. Chromatography (silica gel, 35-40% gradientEtOAc:hexanes) afforded the separated diastereomers. Data for Compound111: ¹H NMR (CDCl₃, 400 MHz) 8.10 (d, 1H, J=9.27 Hz), 6.95 (d, 1H,J=2.92 Hz), 6.69 (dd, 1H, J=2.92 and 9.27 Hz), 4.39 (m, 1H), 4.28 (m,1H), 3.69 (m, 1H), 3.43 (m, 1H), 2.54 (m, 1H), 2.4 (m, 2H), 2.12 (m,2H). Data for Compound 112: ¹H NMR (CDCl₃, 400 MHz) isomer 2: 8.06 (d,1H, J=9.27 Hz), 7.15 (d, 1H, =2.92 Hz), 6.93 (dd, 1H, J=2.92 and 9.27Hz), 4.32 (m, 1H), 3.98 (m, 1H), 3.60 (m, 1H), 3.37 (m, 1H), 2.50 (d,1H, J=3.9 Hz), 2.1-2.3 (m, 4H).

Example 11

(2S)—N-(4-nitrophenyl)-2-(hydroxymethyl)pyrrolidine (Compound 113,Structure 5 of Scheme II, where R¹=nitro, R¹⁰=hydroxymethyl,R²═R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂)

This compound was prepared using the method described in Example 8,except that the S-isomer of Compound 105 was used as the startingmaterial. Data for Compound 113: ¹H NMR (CDCl₃, 500 MHz) 8.08 (d, 2H,J=9.5 Hz), 6.60 (d, 2H, J=9.5 Hz), 4.02 (m, 1H), 3.73 (ddd, 1H, J=11.0,5.7 and 4.2 Hz), 3.64 (ddd, 1H, J=11.0, 7.0 and 5.7 Hz), 3.55 (m, 1H),3.30 (dt, 1H, J=10.3 and 7.8 Hz), 2.11 (m, 4H), 1.73 (t, 1H, J=5.7 Hz).

Example 12

(2R)—N-(4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(Compound 114, Structure 5 of Scheme II, where R¹=nitro,R¹⁰=1-(S)-hydroxy-2, 2,2-trifluoroethyl,R²═R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂) and(2R)—N-(4-nitrophenyl)-2-(R)-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(Compound 115, Structure 5 of Scheme II, where R¹=nitro,R¹⁰=1-(R)-hydroxy-2,2,2-trifluoroethyl,R²═R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂)

To prepare these compounds, first Compound 109 was oxidized using themethod described in Example 9. The resulting aldehyde was then used inplace of Compound 110 in the method described in Example 10. Data forCompound 114: ¹H NMR (CDCl₃, 400 MHz) 8.14 (m, 2H), 6.57 (m, 2H), 4.45(m, 1H), 4.26 (m, 1H), 3.68 (m, 1H), 3.41 (m, 1H), 2.53 (d, 1H, J=5.37Hz), 2.45 (m, 1H), 2.38 (m, 1H), 2.0-2.2 (m, 2H). Data for Compound 115:¹H NMR (CDCl₃, 400 MHz) 8.16 (m, 2H), 6.85 (m, 2H), 4.35 (m, 1H), 3.95(m, 1H), 3.68 (m, 1H), 3.36 (m, 1H), 2.56 (br s, 1H), 2.24 (m, 1H),2.1-2.2 (m, 3H).

Example 13

(2S)—N-(4-nitrophenyl)-2-(1-(s)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(Compound 116, Structure 5 of Scheme II, where R¹=nitro,R¹⁰=1-(S)-hydroxy-2, 2,2-trifluoroethyl,R²═R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂) and(2S)—N-(4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(Compound 117, Structure 5 of Scheme II, where R¹=nitro,R¹⁰=1-(R)-hydroxy-2,2,2-trifluoroethyl,R²═R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂)

To prepare these compounds, Compound 113 was oxidized using the methoddescribed Example 9 and the resulting compound was then used in place ofCompound 110 in the method described in Example 10. Data for Compound116: ¹H NMR (CDCl₃, 400 MHz) 8.09 (m, 2H), 6.75 (m, 2H), 4.46 (m, 1H),4.26 (br d, 1H, J=7.32 Hz), 3.66 (m, 1H), 3.45 (m, 1H), 2.70 (d, 1H,J=5.37 Hz), 2.55 (m, 1H), 2.38 (m, 1H), 2.0-2.15 (m, 2H). Data forCompound 117: ¹H NMR (CDCl₃, 400 MHz) 8.16 (m, 2H), 6.85 (m, 2H), 4.35(m, 1H), 3.95 (m, 1H), 3.68 (m, 1H), 3.36 (m, 1H), 2.55 (d, 1H, J=3.90Hz), 2.24 (m, 1H), 2.1-2.2 (m, 3H).

Example 14

3-(3-Methoxyphenyl)-6-nitro-2,7-dimethyl-1H-indole (Compound 118,Structure 8 of Scheme III, where R¹=nitro, R²═R⁶=Me, R⁴═R⁵═H,R⁷=3-methoxyphenyl)

0.5 g (3.3 mmol) of 2-methyl-3-nitroaniline was dissolved in 15 mL ofconcentrated hydrochloric acid with stirring at 0° C. Sodium nitrite(1.6 g, 1.2 eq) in 5 mL water was then added dropwise. Thirty minuteslater, tin chloride dihydrate (1.6 g, 2.1 eq) in 7 mL concentrated HClwas added. The reaction was stirred for 1 hour and then 7 mL of ethanolwas added followed by 3-methoxyphenylacetone (1.3 mL, 2.5 eq). Thereaction mixture was heated in a 100° C. oil bath. After 12 hours, thereaction was cooled, added to 50 mL of water, extracted into ethylacetate (3×50 mL), dried and then concentrated. Chromatography (silica,15-25% ethyl acetate/hexanes) afforded the title compound 0.132 g (15%yield) as a light yellow powder. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (s, 1H);7.87 (d, J=8.8 Hz, 1H); 7.53 (d, J=8.8 Hz, 1H); 7.41 (dd, J=8.3, 7.6 Hz,1H); 7.05 (ddd, J=7.6, 1.6, 1.0 Hz, 1H); 7.00 (dd, J=2.6, 1.6 Hz, 1H);6.91 (ddd, J=8.3, 2.6, 1.0 Hz, 1H); 3.87 (s, 3H); 2.80 (s, 3H); 2.59 (s,3H).

Example 15

4-[Bis-(2,2,2-trifluoroethyl)amino]-2-chloro-3-methyl-benzonitrile(Compound 119, Structure 2 of Scheme I, where R¹=cyano, R²=chloro,R³=Me, R⁶═R⁹=trifluoromethyl, R⁴═R⁵═R⁷═R⁸═R¹⁰═R¹¹═H)

This compound was prepared following the procedure described in example3. ¹H NMR (500 MHz, CDCl₃) 7.54 (d, J=8.3 Hz, 1H); 7.22 (d, J=8.3 Hz,1H); 3.81 (q, J=8.6 Hz, 4H); 2.40 (s, 3H).

Example 16

Cis-2,5-Dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine(Compound 120, Structure 11 of Scheme IV, where R¹=nitro,R²=trifluoromethyl, R⁶═R¹⁰=Me, R³═R⁴═R⁵═R⁷═R⁸═R⁹═R¹¹═H, n=1) andtrans-2,5-dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine(Compound 121, Structure 11 of Scheme IV, where R¹=nitro,R²=trifluoromethyl, R⁷═R¹⁰=Me, R³═R⁴═R⁵═R⁶═R⁸═R⁹═R¹¹═H, n=1)

To a solution of 4-fluoro-2-(trifluoromethyl)nitrobenzene in 5 mL DMFwas added 2,5-dimethylpyrrolidine (mixture of cis and trans isomers)followed by K₂CO₃. The mixture was stirred at room temperature for 30minutes, and water was slowly added. The yellow precipitate was filteredand rinsed with water. The mixture of cis and trans dimethylpyrrolidineswas partially separated by reverse phase HPLC. Data for compound 120: ¹HNMR (500 MHz, CDCl₃) 8.07 (d, J=9.3 Hz, 1H) 6.88 (d, J=2.7 Hz, 1H) 6.63(dd, J=9.3, 2.7 Hz, 1H) 3.99-3.91 (m, 2H) 2.22-2.14 (m, 2H) 1.88-1.80(m, 2H) 1.33 (d, J=6.3 Hz, 6H) Data for compound 121: ¹H NMR (500 MHz,CDCl₃) 8.07 (d, J=9.3 Hz, 1H) 6.85 (d, J=2.9 Hz, 1H) 6.61 (dd, J=9.3,2.9 Hz, 1H) 4.14-4.09 (m, 2H) 2.35-2.26 (m, 2H) 1.76 (d, J=5.4 Hz, 1H)1.33 (d, J=6.4 Hz, 1H) 1.17 (d, J=6.4 Hz, 6H).

Example 17

1-(4-Nitro-3-trifluoromethylphenyl)-piperidine-2-carboxylic acid ethylester (Compound 122, Structure 11 of Scheme IV, where R¹=nitro,R²=trifluoromethyl, R⁶=ethylcarboxylate, R³═R⁴═R⁵═R⁷═R⁸═R⁹═R¹¹═H, n=2)

This compound was prepared using the method described in Example 16.Data for Compound 122: ¹H NMR (CDCl₃, 500 MHz) 8.02 (d, J=9.1 Hz, 1H)7.15 (d, J=2.9 Hz, 1H) 6.91 (dd, J=9.1, 2.9 Hz, 1H) 4.66 (d, J=3.9 Hz,1H) 4.18 (q, J=7.3 Hz, 2H) 3.78-3.73 (m, 1H) 3.31 (dt, J=3.5, 12.3 Hz,1H) 2.38-2.33 (m, 1H) 1.97-1.82 (m, 2H) 1.81-1.71 (m, 2H) 1.66-1.58 (m,3H) 1.50-1.40 (m, 1H) 1.24 (t, J=7.3 Hz, 1H).

Example 18

1-(4-Nitro-3-trifluoromethylphenyl)-4-(hydroxymethyl)-piperidine(Compound 123, Structure 11 of Scheme IV, where R¹=nitro,R²=trifluoromethyl, R⁶=hydroxymethyl, R³═R⁴═R⁵═R⁷═R⁸═R⁹═R¹¹═H, n=2)

This compound was prepared by reduction of compound 122 with lithiumaluminum hydride. Data for Compound 123: ¹H NMR (CDCl₃, 500 MHz) 8.03(d, J=9.3 Hz, 1H) 7.20 (d, J=2.9 Hz, 1H) 6.98 (dd, J=9.3, 2.9 Hz, 1H)4.27-4.20 (m, 1H) 3.96-3.90 (m, 1H) 3.82-3.73 (m, 1H) 3.23-3.13 (m, 1H)1.92-1.51 (m, 7H).

Example 19

(1-(3-trifluoromethyl-4-nitrophenyl)piperidin-2-yl)methyl acetate(Compound 124, Structure 11 of Scheme IV, where R¹=nitro,R²=trifluoromethyl, R⁶=acetoxymethyl, R³═R⁴═R⁵═R⁷═R⁸═R⁹═R¹¹═H, n=2)

This compound was prepared by acetylation of compound 123 with aceticanhydride. Data for Compound 124: ¹H NMR (CDCl₃, 500 MHz) 8.03 (d, J=9.3Hz, 1H) 7.19 (d, J=2.9 Hz, 1H) 6.94 (dd, J=9.3, 2.9 Hz, 1H) 4.54 (dd,J=11.2, 8.8 Hz, 1H) 4.46-4.39 (m, 1H) 4.09 (dd, J=11.2, 5.8 Hz, 1H)3.73-3.67 (m, 1H) 3.19 (dt, J=3.4, 12.7 Hz, 1H) 1.88-1.71 (m, 4H) 1.85(s, 3H) 1.67-1.60 (m, 2H).

Example 20

4-(2-Hydroxymethyl-pyrrolidin-1-yl)-benzonitrile (Compound 125,Structure 5 of Scheme II, where R¹=cyano, R⁶=hydroxymethyl,R²═R³═R⁴═R⁵═R⁷═R⁸═R⁹═R¹¹═H, n=0, Z=CH₂)

Prepared as in compound 108 of example 7 from(2R)—N-(4-cyanophenyl)-2-(dimethyl-tert-butylsilyloxymethyl)pyrrolidine.¹H NMR (CDCl₃, 500 MHz) 7.46 (d, 2H, J=9.0 Hz), 6.65 (d, 2H, J=9.0 Hz),3.94 (dt, 1H, J=4.4, 6.8 Hz), 3.70 (ddd, 1H, J=5.7, 6.8, 10.9 Hz), 3.61(ddd, J=10.9, 5.7, 4.4 Hz, 1H), 3.50 (m, 1H), 3.22 (m, 1H), 2.15-2.01(m, 4H), 1.55 (t, J=5.7 Hz, 1H).

Example 21

4-Benzyl-2-hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine(Compound 126, Structure 5 of Scheme II, where R¹=nitro,R²=trifluoromethyl, R¹⁰=hydroxymethyl, R¹²=benzyl,R³═R⁴═R⁵═R⁶═R⁷═R⁸═R⁹═R¹¹═H, n=0, Z=CH₂)

Prepared as in compound 108 from example 7. ¹H NMR (CDCl₃, 500 MHz) 8.03(d, J=9.3 Hz, 1H), 7.34 (td, J=7.6, 1.5 Hz, 2H), 7.26 (tt, J=7.6, 1.5Hz, 1H), 7.21 (dd, J=7.6, 1.5 Hz, 2H), 6.92 (d, J=2.7 Hz, 1H), 6.69 (dd,J=9.3, 2.7 Hz, 1H), 4.07 (m, 1H), 3.72 (dt, J=11.0, 5.4 Hz, 1H), 3.66(ddd, J=11.0, 6.6, 5.4 Hz, 1H), 3.61 (dd, J=9.7, 7.2 Hz, 1H), 3.02 (t,J=9.7 Hz, 1H), 2.84 (m, 1H), 2.79 (m, 2H), 2.18 (dd, J=12.7, 5.7 Hz,1H), 1.87 (ddd, J=12.7, 11.0, 8.1 Hz, 1H), 1.55 (t, J=5.4 Hz, 1H).

Example 22

2-Fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-benzonitrile (Compound 127,Structure 5 of Scheme II, where R¹=cyano, R²=fluoro, R¹⁰=hydroxymethyl,R³═R⁴═R⁵═R⁶═R⁷═R⁸═R⁹═R¹¹═H, n=0, Z=CH₂)

Prepared as in compound 108 from example 7. ¹H NMR (CDCl₃, 500 MHz) 7.35(dd, J=8.8, 7.8 Hz, 1H), 6.44 (dd, J=8.8, 2.4 Hz, 1H), 6.37 (dd, J=12.7,2.4 Hz, 1H), 3.92 (m, 1H), 3.70 (m, 1H), 3.62 (m, 1H), 3.47 (m, 1H),3.22 (m, 1H), 2.16-2.01 (m, 4H).

Example 23

4-Hydroxy-1-(4-nitrophenyl)-pyrrolidine-2-carboxylic acid ethyl ester(Compound 128, Structure 5 of Scheme II, where R¹=nitro, R¹²=hydroxyl,R¹⁰=ethylcarboxylate, R²═R³═R⁴═R⁵═R⁶═R⁷═R⁸═R⁹═R¹¹═H, n=0, Z=CH₂)

4-Fluoronitrobenzene (0.28 mL, 2.65 mmol),4-hydroxy-pyrrolidine-2-carboxylic acid ethyl ester (419 mg, 2.65 mmol),and sodium bicarbonate (222 mg, 2.65 mmol) were dissolved in 5 mL dryDMF and heated to 80° C. After 24 h at this temperature, the reactionwas cooled and water and ethyl acetate were added. The organic phasewashed with brine, dried (MgSO₄), and concentrated. Flash chromatography(65-75% ethyl acetate/hexanes) gave 260 mg (35% yield) of the desiredproduct. ¹H NMR (CDCl₃, 500 MHz) 8.15 (d, J=9.3 Hz, 2H), 6.54 (d, J=9.3Hz, 2H), 4.60 (m, 1H), 4.41 (d, J=9.2 Hz, 1H), 4.31 (dq, J=10.8, 7.1 Hz,1H), 4.29 (dq, J=10.8, 7.1 Hz, 1H), 3.73 (dt, J=11.0, 1.2 Hz, 1H), 3.70(dd, J=11.0, 4.2 Hz, 1H), 2.51 (ddd, J=14.2, 9.2, 4.2 Hz, 1H), 2.35 (dd,J=14.2, 1.2 Hz, 1H), 1.34 (t, J=7.1 Hz, 3H).

Example 24

4-Hydroxy-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine-2-carboxylicacid ethyl ester (Compound 129, Structure 5 of Scheme II, whereR¹=nitro, R²=trifluoromethyl R¹²=hydroxyl, R¹⁰=ethylcarboxylate,R³═R⁴═R⁵═R⁶═R⁷═R⁸═R⁹═R¹¹═H, n=0, Z=CH₂)

Prepared as in example 23. ¹H NMR (CDCl₃, 500 MHz) 8.06 (d, J=9.1 Hz,1H), 6.92 (d, J=2.6 Hz, 1H), 6.67 (dd, J=9.1, 2.6 Hz, 1H), 4.62 (m, 1H),4.43 (dd, J=9.4, 1.0 Hz, 1H), 4.34 (dq, J=10.7, 7.2 Hz, 1H), 4.27 (dq,J=10.7, 7.2 Hz, 1H), 3.75-3.68 (m, 2H), 2.52 (ddd, J=14.2, 9.4, 4.8 Hz,1H), 2.39 (ddd, J=14.2, 2.2, 1.0 Hz, 1H), 1.34 (t, J=7.2 Hz, 3H).

Example 25

5-Hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidin-3-ol(Compound 130, Structure 5 of Scheme II, where R¹=nitro,R²=trifluoromethyl, R¹²=hydroxyl, R¹⁰=hydroxymethyl,R³═R⁴═R⁵═R⁶═R⁷═R⁸═R⁹═R¹¹═H, n=0, Z=CH₂)

Compound 129 (75 mg, 0.21 mmol) was dissolved in 2 mL dry THF and cooledto 0° C. under N₂ atmosphere. LAH was added (0.43 mL of a 1.0M solutionin THF) and the reaction was stirred for 10 min. as judged complete byTLC. Careful quenching with Rochelle's salt was followed by anextractive workup. Flash chromatography (5% MeOH/CH₂Cl₂) gave 18 mg(25%) of the product as a yellow oil. ¹H NMR (CDCl₃, 500 MHz) 8.02 (d,J=9.2 Hz, 1H), 6.89 (d, J=2.7 Hz, 1H), 6.66 (dd, J=9.2, 2.7 Hz, 1H),4.57 (m, 2H), 4.22-4.17 (m, 2H), 3.75 (m, 1H), 3.62 (m, 2H), 2.86 (br s,1H), 2.55 (ddd, J=14.3, 9.8, 5.0 Hz, 1H), 2.16 (d, J=14.3 Hz, 1H).

Example 26

2-(Aminomethyl)-1-(4-Nitro-3-trifluoromethylphenyl)-pyrrolidine(Compound 131, Structure 5 of Scheme II, where R¹=nitro,R²=trifluoromethyl, R¹⁰=aminomethyl,R³═R⁴═R⁵═R^(6a)═R^(7a)═R⁹═R¹²═R¹³═H, n=0, Z=CH₂)

To a solution of aldehyde 110 from example 9 (359 mg, 1.24 mmol) in 8 mLdry MeOH was added ammonium acetate (480 mg, 6.22 mmol) followed byNaCNBH₃ (155 mg, 2.48 mmol) at ambient temperature. The reaction wasstirred for 24 h at this temperature and then concentrated to ca. 4 mLin vacuo and diluted with saturated aqueous NaHCO₃. Water and ethylacetate were added and the organic phase washed with brine, dried(MgSO₄), and concentrated. Flash chromatography (65-90% ethylacetate/hexanes) gave 210 mg (59% yield) of the product as a yellowsolid. ¹H NMR (CDCl₃, 500 MHz) 8.03 (d, J=9.0 Hz, 1H), 6.96 (d, J=2.9Hz, 1H), 6.67 (dd, J=9.0, 2.9 Hz, 1H, 3.97 (m, 1H), 3.50 (ddd, J=9.8,6.4, 3.7 Hz, 1H), 3.29 (dt, J=9.8, 8.4 Hz, 1H), 2.78 (dd, J=12.2, 4.9Hz, 1H), 2.69 (dd, J=12.2, 7.8 Hz, 1H), 2.15-2.03 (m, 4H).

Example 27

4-Hydroxy-1-(4-nitrophenyl)-pyrrolidine-2-carboxylic acid (Compound 132,Structure 5 of Scheme II, where R¹=nitro, R¹²=hydroxyl, R¹⁰=carboxylicacid, R²═R³═R⁴═R⁵═R⁶═R⁷═R⁸═R⁹═R¹¹═H, n=0, Z=CH₂)

Compound 128 (70 mg, 0.25 mmol) was dissolved in 3 mL EtOH and KOH (28mg, 0.5 mmol) was added. The reaction was heated to reflux and stirredfor 2 h. The reaction was cooled to room temperature and concentrated invacuo. 10% NaOH (5 mL) was added and extracted with CH₂Cl₂ (2 times).The aqueous phase was adjusted to ˜pH 2 with 10% HCl, and then wasextracted with ethyl acetate (2 times). The organic layers werecombined, dried (MgSO₄), and concentrated. 10 mg of the crude materialwas purified using preparatory HPLC (30:70 water/MeOH) to give compound132. ¹H NMR (Acetone-d₆, 500 MHz) 8.09 (d, J=9.3 Hz, 2H), 6.69 (d, J=9.3Hz, 2H), 4.65 (m, 1H), 4.55 (dd, J=9.3, 1.2 Hz, 1H), 3.72 (dd, J=11.0,4.6 Hz, 1H), 3.60 (d, J=11.0 Hz, 1H), 2.58 (ddd, J=13.5, 9.3, 4.6 Hz,1H), 2.41 (dd, J=13.5, 1.2 Hz, 1H).

Example 28

4-Hydroxy-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine-2-carboxylicacid (Compound 133, Structure 5 of Scheme II, where R¹=nitro,R²=trifluoromethyl R¹²=hydroxyl, R¹⁰-carboxylic acid,R³═R⁴═R⁵═R⁶═R⁷═R⁸═R⁹═R¹¹═H, n=0, Z=CH₂)

Prepared as in example 27. ¹H NMR (Acetone-d₆, 500 MHz) 8.09 (d, J=9.2Hz, 1H), 7.01 (d, J=2.7 Hz, 1H), 6.91 (dd, J=9.2, 2.7 Hz, 1H), 4.69 (dd,J=8.9, 1.8 Hz, 1H), 4.67 (m, 1H), 3.78 (dd, J=11.0, 4.5 Hz, 1H), 3.63(dt, J=11.0, 1.3 Hz, 1H), 2.58 (ddd, J=13.4, 8.9, 4.5 Hz, 1H), 2.47 (dd,J=13.4, 1.8 Hz, 1H).

Example 29

4-Fluoro-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine-2-carboxylicacid ethyl ester (Compound 134, Structure 5 of Scheme II, whereR¹=nitro, R²=trifluoromethyl R¹²=fluoro, R¹⁰=ethylcarboxylate,R³═R⁴═R⁵═R⁶═R⁷═R⁸═R⁹═R¹¹═H, n=0, Z=CH₂)

Compound 129 (66 mg, 0.19 mmol) was dissolved in 2 mL dry CH₂Cl₂ andcooled to −78° C. DAST (0.05 mL, 0.57 mmol) was added via syringe andstirring was continued at this temperature for 1 hour. The cooling bathwas removed, allowing the reaction to reach ambient temperature, andstirring was continued for an additional 1 hour. The reaction wasquenched with NaHCO₃ and ethyl acetate was added. The organic phase wasseparated, dried (MgSO₄), and concentrated. Preparatory HPLC (20:80water/acetonitrile) gave 10 mg (15% yield) of the desired product. ¹HNMR (CDCl₃, 500 MHz) 8.05 (d, J=9.2 Hz, 1H), 6.87 (d, J=2.7 Hz, 1H),6.65 (dd, J=9.2, 2.7 Hz, 1H), 5.45 (dm, J=52.5 Hz, 1H), 4.61 (t, J=7.8Hz, 1H), 4.27 (dq, J=10.8, 7.1 Hz, 1H), 4.20 (dq, J=10.8, 7.1 Hz, 1H),3.96-3.81 (m, 2H), 2.83 (dddt, J=20.2, 14.4, 7.8, 1.9 Hz, 1H), 2.40(dddd, J=35.1, 14.4, 7.8, 4.4 Hz, 1H), 1.27 (t, J=7.1 Hz, 3H).

Example 30

1-(4-Nitro-3-trifluoromethylphenyl)-pyrrolidine-2-carboxylic acid ethylester (Compound 133, Structure 5 of Scheme II, where R¹=nitro,R²=trifluoromethyl R¹⁰=ethylcarboxylate, R³═R⁴═R⁵═R⁶═R⁷═R⁸═R⁹═R¹¹═R¹²═H,n=0, Z=CH₂)

Prepared as in example 16. ¹H NMR (CDCl₃, 500 MHz) 8.05 (d, 1H, J=9.2Hz), 6.85 (d, 1H, J=2.6 Hz), 6.60 (dd, 1H, J=2.6, 9.2 Hz), 4.37 (dd, 1H,J=2.4, 8.5 Hz), 4.25 (dq, 1H, J=7.1, 10.8 Hz), 4.19 (dq, 1H, J=7.1, 10.8Hz), 3.68 (m, 1H), 3.50 (m, 1H), 2.37 (m, 1H), 2.31-2.11 (m, 3H), 1.27(t, 3H, J=7.1 Hz).

Example 31

3-Ethyl-4-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonitrile(Compound 136, Structure 14 of Scheme V, where R¹=cyano,R⁸=2,2,2-trifluoroethyl, R⁶=ethyl, R²═R³═R⁵═R⁷═R¹²═R¹³═H)

Step A 3-Fluoro-4-(1-hydroxymethyl-propylamino)-benzonitrile

A 100 mL round bottom flask was charged with 3,4-difluorobenzonitrile(2.013 g, 14.5 mmol), sodium bicarbonate (1.59 g, 18.9 mmol), andL-(−)-2-amino-1-butanol (1.33 mL, 14.5 mmol). The contents were thendissolved in 40 mL N,N-dimethylformamide (anhydrous). The flask washeated to 90° C. and stirred overnight under N₂. The reaction mixturewas cooled to room temperature, poured onto water, and extracted withEtOAc (2 times). The organic layers were combined, washed with brine,dried (MgSO₄), and concentrated. The resulting residue was purified viasilica gel chromatography (gradient from 5% EtOAc/Hexanes to 10%EtOAc/Hexanes followed by 50% EtOAc/Hexanes) to afford 1.00 g (33%yield) of the title compound. ¹H NMR (CDCl₃, 500 MHz) δ: 7.28 (m, 1H),7.21 (dd, J=11.3, 1.8 Hz, 1H), 6.72 (t, J=8.5 Hz, 1H), 4.49 (s, 1H),3.77 (m, 1H), 3.68 (dt, J=10.0, 5.3 Hz, 1H), 3.48 (m, 1H), 1.87 (m, 1H),1.72 (dqn, J=14.5, 7.5 Hz, 1H), 1.60 (dqn, J=14.5, 7.5 Hz, 1H), 1.00 (t,J=7.5 Hz, 3H).

Step B4-(N-(2,2,2-trifluoroethyl)-N-(1-hydroxybut-2-yl)amino)-3-fluorobenzonitrile

A 25 mL round bottom flask fitted with a Dean-Stark trap, refluxcondenser, and N₂ line was charged with 245.3 mg (1.17 mmol) of3-Fluoro-4-(1-hydroxymethyl-propylamino)-benzonitrile. p-Toluenesulfonicacid (27.4 mg, 0.144 mmol) was then added, along withtrifluoroacetaldehyde ethyl hemiacetal (859.2 mg, 5.96 mmol) in 4 mLtoluene. Toluene was then added to the Dean-Stark trap and the reactionwas heated in an oil bath at 125° C. overnight. The reaction was cooledto room temperature, poured onto water, and the water extracted withEtOAc (2×). The organic layers were combined, washed with brine, dried(MgSO₄), and concentrated. The resulting residue was purified via silicagel chromatography (10% EtOAc/Hexanes) to afford 277.8 mg (82%) of4-(4-Ethyl-2-trifluoromethyl-oxazolidin-3-yl)-3-fluoro-benzonitrile as amixture of diastereomers. This was dissolved in 8 mL CHCl₃ (8 mL) andEt₃SiH (0.62 mL, 3.88 mmol) was then added via syringe and the resultingsolution was cooled to −78° C. TiCl₄ (1M in dichloromethane, 1.95 mL)was then added dropwise via syringe. The reaction was slowly warmed toroom temperature and stirred for 18 hours. The reaction mixture waspoured onto water, and the water extracted with EtOAc (2×). The organiclayers were combined, washed with brine, dried (MgSO₄), andconcentrated. The resulting residue was purified via silica gelchromatography (gradient from 5% EtOAc/Hexanes to 15% EtOAc/Hexanesfollowed by 50% EtOAc/Hexanes) to afford 99.8 mg (36% yield) of4-(N-(2,2,2-trifluoroethyl)-N-(1-hydroxybut-2-yl)amino)-3-fluorobenzonitrile.¹H NMR (CDCl₃, 500 MHz) δ: 7.39-7.34 (m, 2H), 7.32 (m, 1H), 4.05 (m,1H), 3.83 (m, 1H), 3.73 (m, 1H), 3.65 (m, 1H), 3.46 (m, 1H), 1.96 (m,1H), 1.55 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

Step C3-Ethyl-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonitrile

A 25 mL round bottom flask was charged with sodium hydride (60%dispersion in mineral oil, 29 mg, 1.21 mmol) which was then suspended in3 mL THF (anhydrous). To the reaction mixture was then added4-(N-(2,2,2-trifluoroethyl)-N-(1-hydroxybut-2-yl)amino)-3-fluorobenzonitrile(99.8 mg, 0.344 mmol) via syringe in 5 mL THF. The flask was heated to50° C. and stirred for 5 hours. The flask was then cooled to roomtemperature and stirred overnight. The reaction mixture was then pouredonto water, and the water extracted with EtOAc (2×). The organic layerswere combined, washed with brine, dried (MgSO₄), and concentrated. Theresulting residue was purified via silica gel chromatography (gradientfrom 5% EtOAc/Hexanes to 10% EtOAc/hexanes) to afford 44.9 mg (48%) ofCompound 136. ¹H NMR (CDCl₃, 500 MHz) δ: 7.15 (dd, J=8.5, 2.0 Hz, 1H),7.08 (d, J=2.0 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 4.30 (dd, J=11.0, 2.0Hz, 1H), 4.05 (dq, J=16.4, 8.1 Hz, 1H), 4.00 (ddd, J=11.0, 2.0, 0.5 Hz,1H), 3.75 (dq, J=16.4, 8.9 Hz, 1H), 3.33 (ddt, J=8.2, 6.2, 2.0 Hz, 1H),1.68-1.62 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).

Example 32

2-Methyl-5-nitro-3-propyl-1-(2,2,2-trifluoroethyl)-1H-indole (Compound137, Structure 18 of Scheme VI, where R¹=nitro, R⁷=n-propyl, R⁶=methyl,R⁸=2,2,2-trifluoroethyl, R²═R⁴═R⁵═H)

In a 200 ml 2-neck round bottom flask, equipped with a magnetic stirrerand a cold water condenser, 4-nitrophenylhydrazine was dissolved in 75mL concentrated hydrochloric acid and stirred at room temperature for 15minutes. A solution of 2-hexanone (5 mL) in ethanol (25 mL) was addedslowly and the reaction flask was heated in an oil bath at 105° C. for18 h. The mixture was cooled to room temperature and water (100 mL) wasadded. The mixture was extracted with EtOAc. The organic layer washedwith saturated sodium bicarbonate solution, water, and brine solutionsand evaporated to dryness. The oily residue was absorbed on silica geland purified by silica gel chromatography with 20% EtOAc in Hexanesolution to give 2-methyl-5-nitro-3-propyl-1H-indole. This indoleproduct was dissolved in trifluoroacetic acid (10 mL) and 1 pelletsodium borohydride (0.7 g) was added and the reaction was stirred atroom temperature for 18 h. Water (10 mL) was carefully added and thereaction mixture was extracted twice with EtOAc (15 mL). The organiclayer washed with brine and dried over MgSO₄, and purified by flashcolumn chromatography on silica gel eluted with 20% EtOAc in hexanes togive 280 mg of2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indole.

In a 10 ml round bottom flask, equipped with a magnetic stirrer andunder a dry nitrogen atmosphere, 20 mg of2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoro-ethyl)-2,3-dihydro-1H-indolefrom last step was dissolved in EtOAc (3 mL), and 50 mg of DDQ was addedto the solution and stirred at room temperature until TLC analysis (20%EtOAc in hexanes) showed no more starting material. The reaction mixturewas diluted with ethyl acetate (10 mL) and washed with satured sodiumbicarbonate solution, water, and then brine and dried over MgSO₄. Theorganic layer was absorbed on silica gel and purified by flash columnchromatography, eluting with 10% EtOAc in hexanes. 12 mg of2-methyl-5-nitro-3-propyl-1-(2,2,2-trifluoroethyl)-1H-indole wasobtained. ¹H NMR (500 MHz, CDCl₃) δ 8.50 (d, J=2.0 Hz, 1H), 8.14 (dd,J=9.3, 2.0 Hz, 1H), 7.36 (d, J=9.3 Hz, 1H), 4.69 (q, J=8.5 Hz, 2H), 2.76(t, J=7.6 Hz, 2H), 2.44 (s, 3H), 1.72-1.64 (m, 2H), 2.96 (t, J=7.3 Hz,3H).

Example 33

2,2,6-Trimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (Compound 138,Structure 20 of Scheme VII, where R¹=nitro, R²═R⁶═R⁷=methyl, R³═R⁴═H)

A solution of 2,2,6-trimethyl-1,2,3,4-tetrahydroquinoline (0.66 g, 3.8mmol) in 10 mL of concentrated sulfuric acid was cooled to 0° C. in anice bath. To this solution was added dropwise 1.0 mL 90% fuming nitricacid. The resulting mixture was stirred at 0° C. for 30 min., pouredonto 150 mL of ice-water, neutralized to pH=7 with K₂CO₃ and extractedwith CH₂Cl₂ (3×200 mL). The combined organic layers were washed withwater (2×300 mL), saturated aqueous NaHCO₃ (300 mL) and brine (300 mL).The solution was dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography (Silica gel, 15 to 20% ethyl acetate/hexane gradientelution) to give 2,2,6-trimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline.¹H NMR (500 MHz, CDCl₃): 8.03 (s, 1H), 7.05 (s, 1H), 2.85 (td, J=6.6,1.1 Hz, 2H), 2.17 (s, 3H), 1.76 (t, J=6.6 Hz, 2H), 1.35 (s, 6H).

While description of the exemplary embodiments and processing conditionshave been provided, the scope of the claimed subject matter is not to belimited thereto or thereby. Various modifications and alterations of theclaimed subject matter will be apparent to those skilled in the artwithout departing from the scope and spirit of the claimed subjectmatter.

1. A compound of Formula I, Formula II, Formula III, Formula IV, FormulaV, or Formula VI:

wherein: R¹ and R² each independently is selected from among hydrogen,F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄alkyl, an optionally substituted C₁-C₄ haloalkyl, an optionallysubstituted C₁-C₄ heteroalkyl, COR^(A), CO₂R^(A), CONR^(A)R^(B),SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B), NHCOR^(A), and NHCONR^(A)R^(B),provided that at least one of R¹ and R² is not hydrogen; R³, R^(3a), R⁴,and R⁵ each independently is selected from among hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl; provided that if R¹ is NO₂ and R^(3a) is F,then at least one of R² and R⁴ and R⁵ is not hydrogen; and provided thatif R¹ is NO₂ and R³ is F, then Z is not O; R⁶, R⁷, R¹⁰, and R¹¹ eachindependently is selected from among hydrogen, an optionally substitutedC₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, an optionallysubstituted C₁-C₆ heteroalkyl, an optionally substituted C₂-C₆ alkynyl,and an optionally substituted C₂-C₆ alkenyl; R^(6a) and R^(7a) eachindependently is selected from among hydrogen, an optionally substitutedC₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, an optionallysubstituted C₁-C₆ heteroalkyl, an optionally substituted C₂-C₆ alkynyl,and an optionally substituted C₂-C₆ alkenyl; or R^(6a) and R^(7a)together form a carbonyl; R⁸ and R⁹ each independently is selected fromamong hydrogen, an optionally substituted C₁-C₈ alkyl, an optionallysubstituted C₂-C₈ alkenyl, an optionally substituted C₁-C₈ haloalkyl, anoptionally substituted C₂-C₈ haloalkenyl, C₁-C₈ heteroalkyl, anoptionally substituted C₂-C₈ heteroalkenyl, an optionally substitutedC₂-C₈ alkynyl, an optionally substituted C₂-C₈ haloalkynyl, anoptionally substituted C₂-C₈ heteroalkynyl, an optionally substitutedaryl, an optionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C); R¹² and R¹³ each independentlyis selected from among hydrogen, F, Cl, OR^(A), NR^(A)R^(B), SR^(A), anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionallysubstituted C₂-C₆ alkynyl, an optionally substituted C₂-C₆ alkenyl, and(CH₂)_(m)R^(C); R¹⁴ and R¹⁵ each independently is selected from amonghydrogen, F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, anoptionally substituted C₁-C₄ heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B),COR^(A), CO₂R^(A), CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B);R¹⁶ and R¹⁷ each independently is selected from among hydrogen, F, Cl,OR^(A), an optionally substituted C₁-C₄ alkyl, and an optionallysubstituted C₁-C₄ haloalkyl; R¹⁸ and R¹⁹ each independently is selectedfrom among hydrogen, F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, an optionally substituted C₁-C₄ heteroalkyl, NHCOR^(A),NHCONR^(A)R^(B), COR^(A), CO₂R^(A), CONR^(A)R^(B), SOR^(A), SO₂R^(A),and SO₂NR^(A)R^(B); R²⁰ and R²¹ each independently is selected fromamong hydrogen, F, Cl, OR^(A), an optionally substituted C₁-C₄ alkyl,and an optionally substituted C₁-C₄ haloalkyl; wherein if R¹⁸ is NO₂ andX is O, then at least one of R¹⁹, R²⁰, and R²¹ is not hydrogen, andwherein if R¹⁹ is NO₂ and X is C, then at least one of R¹⁸, R²⁰, and R²¹is not hydrogen; R²² is selected from among hydrogen, an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, anoptionally substituted C₁-C₄ heteroalkyl, COR⁶, CO₂R^(A), CONR^(A)R^(B),SO₂R^(A), an optionally substituted aryl, an optionally substitutedheteroaryl, CH₂CH(R^(D))OR^(A), CH₂CH(R^(D))NR^(A)R^(B), and(CH₂)_(m)R^(C), wherein the optionally substituted aryl or optionallysubstituted heteroaryl is optionally substituted with a substituentselected from among F, Cl, Br, I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A),SOR^(A), SO₂R^(A), an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl; R²³ and R²⁴ each independently is selected from amonghydrogen, an optionally substituted C₁-C₈ alkyl, an optionallysubstituted C₂-C₈ alkenyl, an optionally substituted C₁-C₈ haloalkyl, anoptionally substituted C₂-C₈ haloalkenyl, an optionally substitutedC₁-C₈ heteroalkyl, an optionally substituted C₂-C₈ heteroalkenyl, anoptionally substituted C₂-C₈ alkynyl, an optionally substituted C₂-C₈haloalkynyl, an optionally substituted C₂-C₈ heteroalkynyl, anoptionally substituted aryl, an optionally substituted heteroaryl,CH(R^(D))OR^(A), CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C); or R²³ andR²⁴ together form a carbonyl group, provided that if R¹⁸ is NO₂ and X isNH, then R²³ and R²⁴ do not together form a carbonyl group; R²² and R²³are optionally linked to form a ring; R²³ and R²⁵ are optionally linkedto form a ring; X is selected from among O, S, CR^(A)R^(B), NR^(D), anda bond; wherein if X is CR^(A)R^(B) or a bond, then R²⁵ and R²⁶ eachindependently is selected from among a halogen, OR^(A), NR^(A)R^(B),hydrogen, an optionally substituted C₁-C₈ alkyl, an optionallysubstituted C₂-C₈ alkenyl, an optionally substituted C₁-C₈ haloalkyl, anoptionally substituted C₂-C₈ haloalkenyl, an optionally substitutedC₁-C₈ heteroalkyl, an optionally substituted C₂-C₈ heteroalkenyl, anoptionally substituted C₂-C₈ alkynyl, an optionally substituted C₂-C₈haloalkynyl, an optionally substituted C₂-C₈ heteroalkynyl, anoptionally substituted aryl, an optionally substituted heteroaryl, and(CH₂)_(m)R^(C); or R²⁵ and R²⁶ together form a carbonyl group; andwherein if X is selected from among O, S, or NR^(D), then R²⁵ and R²⁶each independently is selected from among hydrogen, an optionallysubstituted C₁-C₈ alkyl, an optionally substituted C₂-C₈ alkenyl, anoptionally substituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, an optionally substituted C₁-C₈ heteroalkyl, an optionallysubstituted C₂-C₈ heteroalkenyl, an optionally substituted C₂-C₈alkynyl, an optionally substituted C₂-C₈ haloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, and (CH₂)_(m)R^(C); or R²⁵ and R²⁶together form a carbonyl group; R^(A) and R^(B) each independently isselected from among hydrogen, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl; R^(C) is selected from among an optionallysubstituted aryl and an optionally substituted heteroaryl that isoptionally substituted with a substituent selected from among F, Cl, Br,I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A), SO₂R^(A), anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, and an optionally substituted C₁-C₄ heteroalkyl; R^(D) isselected from among hydrogen, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl; Z is selected from among O, S, CR^(A)R^(B), andNR^(D); n is 0, 1, or 2; and m is 1 or 2; or a pharmaceuticallyacceptable salt, ester, amide or prodrug thereof.
 2. The compound ofclaim 1 of Formula II or Formula IV:

wherein: R¹ and R² each independently is selected from among hydrogen,F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄alkyl, an optionally substituted C₁-C₄ haloalkyl, an optionallysubstituted C₁-C₄ heteroalkyl, COR^(A), CO₂R^(A), CONR^(A)R^(B),SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B), NHCOR^(A), and NHCONR^(A)R^(B),provided that at least one of R¹ and R² is not hydrogen; R³, R⁴, and R⁵each independently is selected from among hydrogen, F, Cl, OR^(A), anoptionally substituted C₁-C₄ alkyl, and an optionally substituted C₁-C₄haloalkyl; provided that if R¹ is NO₂ and R³ is F, then Z is not O; R⁶,R⁷, and R¹⁰ each independently is selected from among hydrogen, anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl, an optionally substituted C₂-C₆heterohaloalkenyl, an optionally substituted C₂-C₆ heterohaloalkynyl, anoptionally substituted C₂-C₆ alkynyl, and an optionally substitutedC₂-C₆ alkenyl; R^(6a) and R^(7a) each independently is selected fromamong hydrogen, an optionally substituted C₁-C₆ alkyl, an optionallysubstituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆heteroalkyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ heterohaloalkenyl, an optionallysubstituted C₂-C₆ heterohaloalkynyl, an optionally substituted C₂-C₆alkynyl, and an optionally substituted C₂-C₆ alkenyl; or R^(6a) andR^(7a) together form a carbonyl; R⁹ is selected from among hydrogen, anoptionally substituted C₁-C₈ alkyl, an optionally substituted C₂-C₈alkenyl, an optionally substituted C₁-C₈ haloalkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl, an optionally substituted C₂-C₈haloalkenyl, C₁-C₈ heteroalkyl, an optionally substituted C₂-C₈heteroalkenyl, an optionally substituted C₂-C₈ alkynyl, an optionallysubstituted C₂-C₈ haloalkynyl, an optionally substituted C₂-C₈heteroalkynyl, an optionally substituted C₂-C₆ heterohaloalkenyl, anoptionally substituted C₂-C₆ heterohaloalkynyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), COR^(A), CO₂R^(A) and (CH₂)_(m)R^(C); R¹² and R¹³each independently is selected from among hydrogen, F, Cl, OR^(A),NR^(A)R^(B), SR^(A), an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆heteroalkyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ heterohaloalkenyl, an optionallysubstituted C₂-C₆ heterohaloalkynyl, an optionally substituted C₂-C₆alkynyl, an optionally substituted C₂-C₆ alkenyl, and (CH₂)_(m)R^(C);R¹⁴ and R¹⁵ each independently is selected from among hydrogen, F, Cl,Br, I, OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄ alkyl,an optionally substituted C₁-C₄ haloalkyl, an optionally substitutedC₁-C₄ heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B), COR^(A), CO₂R^(A),CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B); R¹⁶ and R¹⁷ eachindependently is selected from among hydrogen, F, Cl, OR^(A), anoptionally substituted C₁-C₄ alkyl, and an optionally substituted C₁-C₄haloalkyl; R^(A) and R^(B) each independently is selected from amonghydrogen, an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl; R^(C) is selected from among an optionally substituted aryland an optionally substituted heteroaryl that is optionally substitutedwith a substituent selected from among F, Cl, Br, I, CN, OR^(A), NO₂,NR^(A)R^(B), SR^(A), SOR^(A), SO₂R^(A), an optionally substituted C₁-C₄alkyl, an optionally substituted C₁-C₄ haloalkyl, and an optionallysubstituted C₁-C₄ heteroalkyl; R^(D) is selected from among hydrogen, anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, and an optionally substituted C₁-C₄ heteroalkyl; Z isselected from among O, S, CR^(A)R^(B), and NR^(D); n is 0, 1, or 2; andm is 1 or
 2. 3. The compound of claim 1, wherein R¹ is NO₂ or CN.
 4. Thecompound of claim 1, wherein R¹ is NO₂.
 5. The compound of claim 1,wherein R¹ is CN.
 6. The compound of claim 1, wherein R² is anoptionally substituted C₁-C₄ alkyl or an optionally substituted C₁-C₄haloalkyl.
 7. The compound of claim 1, wherein R² is C₁-C₄ alkyl ortrifluoromethyl.
 8. The compound of claim 1, wherein R³, R⁴, and R⁵ eachindependently is selected from among hydrogen, F, Cl, and an optionallysubstituted C₁-C₄ alkyl.
 9. The compound of claim 1, wherein R³ ishydrogen.
 10. The compound of claim 1, wherein R⁴ is hydrogen.
 11. Thecompound of claim 1, wherein R⁵ is hydrogen.
 12. The compound of claim1, wherein R^(6a) and R^(7a) each independently is selected from amonghydrogen, an optionally substituted C₁-C₆ alkyl, and an optionallysubstituted C₁-C₆ heterohaloalkyl or R^(6a) and R^(7a) together form acarbonyl.
 13. The compound of claim 1, wherein R^(6a) is hydrogen. 14.The compound of claim 1, wherein R^(7a) is hydrogen or an optionallysubstituted C₁-C₆ alkyl.
 15. The compound of claim 1, wherein R^(7a) ishydrogen or methyl.
 16. The compound of claim 1, wherein R^(7a) ishydrogen.
 17. The compound of claim 1, wherein R^(7a) is methyl.
 18. Thecompound of claim 1, wherein R^(6a) and R^(7a) together form a carbonyl.19. The compound of claim 1, wherein R¹⁰ is selected from amonghydrogen, F, Cl, OR^(A), an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₁-C₆ heterohaloalkyl and (CH₂)_(m)R^(C).
 20. Thecompound of claim 1, wherein R¹⁰ is hydrogen.
 21. The compound of claim1, wherein R⁹ is selected from among hydrogen, F, Cl, Br, I, anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₆heterohaloalkyl, COR^(A), CO₂R^(A), CH(R^(D))OR^(A), andCH(R^(D))NR^(A)R^(B).
 22. The compound of claim 1, wherein R⁹ ishydrogen, formyl, hydroxy C₁-C₆alkyl, hydroxyhalo C₁-C₆alkyl,C₁-C₆alkylsilyloxy C₁-C₆alkyl, C₁-C₆alkoxycarbonyl, amino C₁-C₆alkyl,carboxy, or C₁-C₆alkylcarbonyloxyC₁-C₆alkyl.
 23. The compound of claim1, wherein R⁹ is hydrogen, formyl, hydroxymethyl,1-hydroxy-2,2,2-trifluoromethyl, tributylsilyloxymethyl, ethoxycarbonyl,aminomethyl, carboxy, or acetyoxymethyl.
 24. The compound of claim 1,wherein R¹² and R¹³ each independently is selected from among hydrogen,F, Cl, OR^(A), an optionally substituted C₁-C₆ alkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl and (CH₂)_(m)R^(C).
 25. The compoundof claim 1, wherein R¹³ is hydrogen, F, OH or benzyl.
 26. The compoundof claim 1 of formula IIA:


27. The compound of claim 1 of formula IIB:


28. The compound of claim 1, wherein R¹ is NO₂ or CN; R² is hydrogen,optionally substituted C₁-C₄ alkyl or an optionally substituted C₁-C₄haloalkyl; R³, R⁴, and R⁵ each independently is selected from amonghydrogen, F, Cl, and an optionally substituted C₁-C₄ alkyl; R^(6a) andR^(7a) each independently is selected from among hydrogen and anoptionally substituted C₁-C₆ alkyl; an optionally substituted C₁-C₆heterohaloalkyl, or R^(6a) and R^(7a) together form a carbonyl; R⁹ isselected from among hydrogen, F, Cl, Br, I, an optionally substitutedC₁-C₄ alkyl, an optionally substituted C₁-C₆ heterohaloalkyl, COR^(A),CO₂R^(A), CH(R^(D))OR^(A), and CH(R^(D))NR^(A)R^(B); R¹⁰ is hydrogen;and R¹² and R¹³ each independently is selected from among hydrogen, F,Cl, OR^(A), an optionally substituted C₁-C₆ alkyl, an optionallysubstituted C₁-C₆ heterohaloalkyl and (CH₂)_(m)R^(C).
 29. The compoundof claim 1, wherein R¹ is NO₂ or CN; R² is hydrogen or trifluoromethyl;R³, R⁴, and R⁵ each is hydrogen; R^(7a) is hydrogen or methyl and R^(6a)is hydrogen; or R^(6a) and R^(7a) together form a carbonyl; R⁹ isselected from among hydrogen, formyl, hydroxymethyl,1-hydroxy-2,2,2-trifluoromethyl, tributylsilyloxymethyl, ethoxycarbonyl,aminomethyl, carboxy, and acetyloxymethyl; R¹⁰ is hydrogen; R¹² ishydrogen; and R¹³ is selected from among hydrogen, F, OH and benzyl. 30.The compound of claim 1, wherein the compound is selected from among:


31. The compound of claim 30, wherein R^(7a) is an optionallysubstituted C₁-C₆ heterohaloalkyl.
 32. The compound of claim 30, whereinR⁹ is an optionally substituted C₁-C₆ heterohaloalkyl.
 33. The compoundof claim 30, wherein R¹³ is an optionally substituted C₁-C₆heterohaloalkyl.
 34. The compound of claim 30, wherein the compound is:


35. The compound of claim 30, wherein the compound is:


36. The compound of claim 1 of Formula IIC or Formula IID:


37. The compound of claim 36, wherein R¹ is NO₂; R₂ is hydrogen orhaloalkyl; R³, R⁴, R⁵, R^(6a), R^(7a), R⁹, R¹², and R¹³ each ishydrogen; and R⁹ is selected from among CO₂R^(A), CH(R^(D))OR^(A), andCH(R^(D))NR^(A)R^(B).
 38. The compound of claim 36, wherein R¹ is NO₂;R₂ is hydrogen or trifluoromethyl; R³, R⁴, R⁵, R^(6a), R^(7a), R⁹, R¹²,and R¹³ each is hydrogen; and R⁹ is selected from among hydroxymethyl,ethoxycarbonyl and acetyoxymethyl.
 39. The compound of claim 1, whereinthe compound is:


40. The compound of claim 1, wherein the compound is:


41. The compound of claim 1, wherein the compound is:


42. The compound of claim 1 of Formula V or Formula VI:

wherein R¹⁸ and R¹⁹ each independently is selected from among hydrogen,F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄alkyl, an optionally substituted C₁-C₄ haloalkyl, an optionallysubstituted C₁-C₄ heteroalkyl, NHCOR^(A), NHCONR^(A)R^(B), COR^(A),CO₂R^(A), CONR^(A)R^(B), SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B); R²⁰ andR²¹ each independently is selected from among hydrogen, F, Cl, OR^(A),an optionally substituted C₁-C₄ alkyl, and an optionally substitutedC₁-C₄ haloalkyl; wherein if R¹⁸ is NO₂ and X is O, then at least one ofR¹⁹, R²⁰, and R²¹ is not hydrogen, and wherein if R¹⁹ is NO₂ and X is C,then at least one of R¹⁸, R²⁰, and R²¹ is not hydrogen; R²² is selectedfrom among hydrogen, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, an optionally substituted C₁-C₄heteroalkyl, an optionally substituted C₁-C₄ heterohaloalkyl, anoptionally substituted C₂-C₆ heterohaloalkenyl, an optionallysubstituted C₂-C₆ heterohaloalkynyl, COR⁶, CO₂R^(A), CONR^(A)R^(B),SO₂R^(A), an optionally substituted aryl, an optionally substitutedheteroaryl, CH₂CH(R^(D))OR^(A), CH₂CH(R^(D))NR^(A)R^(B), and(CH₂)_(m)R^(C), wherein the optionally substituted aryl or optionallysubstituted heteroaryl is optionally substituted with a substituentselected from among F, Cl, Br, I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A),SOR^(A), SO₂R^(A), an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl; R²³ and R²⁴ each independently is selected from amonghydrogen, an optionally substituted C₁-C₈ alkyl, an optionallysubstituted C₂-C₈ alkenyl, an optionally substituted C₁-C₈ haloalkyl, anoptionally substituted C₂-C₈ haloalkenyl, an optionally substitutedC₁-C₈ heteroalkyl, an optionally substituted C₂-C₈ heteroalkenyl, anoptionally substituted C₂-C₈ alkynyl, an optionally substituted C₂-C₈haloalkynyl, an optionally substituted C₂-C₈ heteroalkynyl, anoptionally substituted C₂-C₈ heterohaloalkenyl, an optionallysubstituted C₂-C₈ heterohaloalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C); or R²³ and R²⁴ together form acarbonyl group, provided that if R¹⁸ is NO₂ and X is NH, then R²³ andR²⁴ do not together form a carbonyl group; or R²² and R²³ are optionallylinked to form a ring; or R²³ and R²⁵ are optionally linked to form aring; R²⁵ is selected from among a halogen, OR^(A), NR^(A)R^(B),hydrogen, an optionally substituted C₁-C₈ alkyl, an optionallysubstituted C₂-C₈ alkenyl, an optionally substituted C₁-C₈ haloalkyl, anoptionally substituted C₂-C₈ haloalkenyl, an optionally substitutedC₁-C₈ heteroalkyl, an optionally substituted C₂-C₈ heteroalkenyl, anoptionally substituted C₂-C₈ alkynyl, an optionally substituted C₂-C₈haloalkynyl, an optionally substituted C₂-C₈ heterohaloalkenyl, anoptionally substituted C₂-C₈ heterohaloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, and (CH₂)_(m)R^(C); X is selectedfrom among O, S, CR^(A)R^(B), NR^(D), and a bond; wherein if X isCR^(A)R^(B) or a bond, then R²⁵ and R²⁶ each independently is selectedfrom among a halogen, OR^(A), NR^(A)R^(B), hydrogen, an optionallysubstituted C₁-C₈ alkyl, an optionally substituted C₂-C₈ alkenyl, anoptionally substituted C₁-C₈ haloalkyl, an optionally substituted C₂-C₈haloalkenyl, an optionally substituted C₁-C₈ heteroalkyl, an optionallysubstituted C₂-C₈ heteroalkenyl, an optionally substituted C₂-C₈alkynyl, an optionally substituted C₂-C₈ haloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted C₁-C₆heterohaloalkyl, an optionally substituted C₂-C₆ heterohaloalkenyl, anoptionally substituted C₂-C₆ heterohaloalkynyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, and(CH₂)_(m)R^(C); or R²⁵ and R²⁶ together form a carbonyl group; andwherein if X is O, S, or NR^(D), then R²⁵ and R²⁶ each independently isselected from among hydrogen, an optionally substituted C₁-C₈ alkyl, anoptionally substituted C₂-C₈ alkenyl, an optionally substituted C₁-C₈haloalkyl, an optionally substituted C₂-C₈ haloalkenyl, an optionallysubstituted C₁-C₈ heteroalkyl, an optionally substituted C₂-C₈heteroalkenyl, an optionally substituted C₂-C₈ alkynyl, an optionallysubstituted C₂-C₈ haloalkynyl, an optionally substituted C₂-C₈heteroalkynyl, an optionally substituted C₁-C₆ heterohaloalkyl, anoptionally substituted C₂-C₆ heterohaloalkenyl, an optionallysubstituted C₂-C₆ heterohaloalkynyl, an optionally substituted aryl, anoptionally substituted heteroaryl, and (CH₂)_(m)R^(C); or R²⁵ and R²⁶together form a carbonyl group; R^(A) and R^(B) each independently isselected from among hydrogen, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl; R^(C) is selected from among an optionallysubstituted aryl and an optionally substituted heteroaryl that isoptionally substituted with a substituent selected from among F, Cl, Br,I, CN, OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A), SO₂R^(A), anoptionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, and an optionally substituted C₁-C₄ heteroalkyl; R^(D) isselected from among hydrogen, an optionally substituted C₁-C₄ alkyl, anoptionally substituted C₁-C₄ haloalkyl, and an optionally substitutedC₁-C₄ heteroalkyl; Z is selected from among O, S, CR^(A)R^(B), andNR^(D); n is 0, 1, or 2; and m is 1 or
 2. 43. The compound of claim 1 ofFormula V, wherein n is 1:


44. The compound of claim 1 of Formula V, wherein X is CR^(A)R^(B), andR^(A) and R^(B) each is hydrogen:


45. The compound of claim 1 of Formula V, wherein X is O:


46. The compound of claim 1, wherein R¹⁸ and R¹⁹ each independently isselected from among hydrogen, NO₂, and an optionally substituted C₁-C₄alkyl; R²² is hydrogen, an optionally substituted C₁-C₄ alkyl and anoptionally substituted C₁-C₄ haloalkyl; R²³ and R²⁴ each independentlyis hydrogen or an optionally substituted C₁-C₄ alkyl; and R²⁵ and R²⁶each is hydrogen.
 47. The compound of claim 1, wherein R¹⁸ is NO₂. 48.The compound of claim 1, wherein R¹⁹ is NO₂.
 49. The compound of claim1, wherein R²² is hydrogen, heterohaloalkyl or haloalkyl.
 50. Thecompound of claim 1, wherein R²² is hydrogen or trifluoroethyl.
 51. Thecompound of claim 1, wherein R²³ and R²⁴ each independently is hydrogenor methyl.
 52. The compound of claim 1 of Formula VI:


53. The compound of claim 52, wherein R¹⁸ is NO₂.
 54. The compound ofclaim 53, wherein R¹⁹ is NO₂.
 55. The compound of claim 52, wherein R²²is hydrogen, haloalkyl, an optionally substituted C₁-C₄ heteroalkyl oran optionally substituted C₁-C₄ heterohaloalkyl.
 56. The compound ofclaim 52, wherein R²² is hydrogen or trifluoroethyl.
 57. The compound ofclaim 52, wherein R²³ is hydrogen, an optionally substituted aryl, anoptionally substituted heteroaryl or an optionally substituted C₁-C₄alkyl.
 58. The compound of claim 1, wherein R²⁵ is hydrogen, methyl ormethoxyphenyl.
 59. The compound of claim 1 of Formula III:

wherein: R¹ and R² each independently is selected from among hydrogen,F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄alkyl, an optionally substituted C₁-C₄ haloalkyl, an optionallysubstituted C₁-C₄ heteroalkyl, COR^(A), CO₂R^(A), CONR^(A)R^(B),SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B), NHCOR^(A), and NHCONR^(A)R^(B),provided that at least one of R¹ and R² is not hydrogen; R^(3a), R⁴, andR⁵ each independently is selected from among hydrogen, F, Cl, OR^(A), anoptionally substituted C₁-C₄ alkyl, and an optionally substituted C₁-C₄haloalkyl; provided that if R¹ is NO₂ and R^(3a) is F, then at least oneof R² and R⁴ and R⁵ is not hydrogen; R⁶, R⁷, R¹⁰, and R¹¹ eachindependently is selected from among hydrogen, an optionally substitutedC₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, an optionallysubstituted C₁-C₆ heteroalkyl, an optionally substituted C₁-C₆heterohaloalkyl, an optionally substituted C₂-C₆ heterohaloalkenyl, anoptionally substituted C₂-C₆ heterohaloalkynyl, an optionallysubstituted C₂-C₆ alkynyl, and an optionally substituted C₂-C₆ alkenyl;R⁸ and R⁹ each independently is selected from among hydrogen, anoptionally substituted C₁-C₈ alkyl, an optionally substituted C₂-C₈alkenyl, an optionally substituted C₁-C₈ haloalkyl, an optionallysubstituted C₂-C₈ haloalkenyl, C₁-C₈ heteroalkyl, an optionallysubstituted C₂-C₈ heteroalkenyl, an optionally substituted C₂-C₈alkynyl, an optionally substituted C₂-C₈ haloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted C₁-C₆heterohaloalkyl, an optionally substituted C₂-C₆ heterohaloalkenyl, anoptionally substituted C₂-C₆ heterohaloalkynyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C); R¹⁴ and R¹⁵ each independentlyis selected from among hydrogen, F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN,an optionally substituted C₁-C₄ alkyl, an optionally substituted C₁-C₄haloalkyl, an optionally substituted C₁-C₄ heteroalkyl, NHCOR^(A),NHCONR^(A)R^(B), COR^(A), CO₂R^(A), CONR^(A)R^(B), SOR^(A), SO₂R^(A),and SO₂NR^(A)R^(B); R¹⁶ and R¹⁷ each independently is selected fromamong hydrogen, F, Cl, OR^(A), an optionally substituted C₁-C₄ alkyl,and an optionally substituted C₁-C₄ haloalkyl; R^(A) and R^(B) eachindependently is selected from among hydrogen, an optionally substitutedC₁-C₄ alkyl an optionally substituted C₁-C₄ haloalkyl, and an optionallysubstituted C₁-C₄ heteroalkyl; R^(C) is selected from among anoptionally substituted aryl and a heteroaryl that is optionallysubstituted with a substituent selected from among F, Cl, Br, I, CN,OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A), SO₂R^(A), an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, andan optionally substituted C₁-C₄ heteroalkyl; R^(D) is selected fromamong hydrogen, an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl; and m is 1 or 2; provided that at least one of R⁶, R⁷, R¹⁰,and R¹¹ is other than hydrogen and at least one of R⁸ and R⁹ is otherthan hydrogen, alkyl, haloalkyl, alkenyl, and alkynyl.
 60. The compoundof claim 59, wherein at least one of R⁶, R⁷, R¹⁰, and R¹¹ is other thanhydrogen and at least one of R⁸ and R⁹ is heterohaloalkyl.
 61. Thecompound of claim 1 of Formula I:

wherein: R¹ and R² each independently is selected from among hydrogen,F, Cl, Br, I, OR^(A), SR^(A), NO₂, CN, an optionally substituted C₁-C₄alkyl, an optionally substituted C₁-C₄ haloalkyl, an optionallysubstituted C₁-C₄ heteroalkyl, COR^(A), CO₂R^(A), CONR^(A)R^(B),SOR^(A), SO₂R^(A), and SO₂NR^(A)R^(B), NHCOR^(A), and NHCONR^(A)R^(B),provided that at least one of R¹ and R² is not hydrogen; R^(3a), R⁴, andR⁵ each independently is selected from among hydrogen, F, Cl, OR^(A), anoptionally substituted C₁-C₄ alkyl, and an optionally substituted C₁-C₄haloalkyl; provided that if R¹ is NO₂ and R^(3a) is F, then at least oneof R² and R⁴ and R⁵ is not hydrogen; R⁶, R⁷, R¹⁰, and R¹¹ eachindependently is selected from among hydrogen, an optionally substitutedC₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, an optionallysubstituted C₁-C₆ heteroalkyl, an optionally substituted C₁-C₆heterohaloalkyl, an optionally substituted C₂-C₆ heterohaloalkenyl, anoptionally substituted C₂-C₆ heterohaloalkynyl, an optionallysubstituted C₂-C₆ alkynyl, and an optionally substituted C₂-C₆ alkenyl;R⁸ and R⁹ each independently is selected from among hydrogen, anoptionally substituted C₁-C₈ alkyl, an optionally substituted C₂-C₈alkenyl, an optionally substituted C₁-C₈ haloalkyl, an optionallysubstituted C₂-C₈ haloalkenyl, C₁-C₈ heteroalkyl, an optionallysubstituted C₂-C₈ heteroalkenyl, an optionally substituted C₂-C₈alkynyl, an optionally substituted C₂-C₈ haloalkynyl, an optionallysubstituted C₂-C₈ heteroalkynyl, an optionally substituted C₁-C₆heterohaloalkyl, an optionally substituted C₂-C₆ heterohaloalkenyl, anoptionally substituted C₂-C₆ heterohaloalkynyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, CH(R^(D))OR^(A),CH(R^(D))NR^(A)R^(B), and (CH₂)_(m)R^(C); R^(A) and R^(B) eachindependently is selected from among hydrogen, an optionally substitutedC₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, and anoptionally substituted C₁-C₄ heteroalkyl; R^(C) is selected from amongan optionally substituted aryl and a heteroaryl that is optionallysubstituted with a substituent selected from among F, Cl, Br, I, CN,OR^(A), NO₂, NR^(A)R^(B), SR^(A), SOR^(A), SO₂R^(A), an optionallysubstituted C₁-C₄ alkyl, an optionally substituted C₁-C₄ haloalkyl, andan optionally substituted C₁-C₄ heteroalkyl; R^(D) is selected fromamong hydrogen, an optionally substituted C₁-C₄ alkyl, an optionallysubstituted C₁-C₄ haloalkyl, and an optionally substituted C₁-C₄heteroalkyl; and m is 1 or 2; provided that at least one of R⁶, R⁷, R¹⁰,and R¹¹ is other than hydrogen and at least one of R⁸ and R⁹ isheterohaloalkyl.
 62. A compound of claim 1, wherein the compound isselected from among:N,N-bis(2,2,2-trifluoroethyl)-3-methyl-4-nitroaniline (compound 101);N,N-bis(2,2,2-trifluoroethyl)-4-nitroaniline (compound 102);4-(Bis(2,2,2-trifluoroethyl)amino)-2-(trifluoromethyl)benzonitrile(compound 103);(5R)—N-(4-nitrophenyl)-5-(dimethyl-tert-butylsilyloxymethyl)-2-pyrrolidone(compound 104); (5R)—N-(4-nitrophenyl)-5-(hydroxymethyl)-2-pyrrolidone(compound 105);(2R)—N-(4-nitro-3-trifluoromethylphenyl)-2-(dimethyl-tert-butylsilyloxymethyl)pyrrolidine(compound 106);(2R)—N-(4-nitro-3-trifluoromethylphenyl)-2-(hydroxymethyl)pyrrolidine(compound 108); (2R)—N-(4-nitrophenyl)-2-(hydroxymethyl)pyrrolidine(compound 109);(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine (compound110);(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(compound 111);(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(compound 112); (2S)—N-(4-nitrophenyl)-2-(hydroxymethyl)pyrrolidine(compound 113);(2R)—N-(4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(compound 114);(2R)—N-(4-nitrophenyl)-2-(R)-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(compound 115);(2S)—N-(4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(compound 116);(2S)—N-(4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine(compound 117); 3-(3-Methoxyphenyl)-6-nitro-2,7-dimethyl-1H-indole(compound 118);4-[Bis-(2,2,2-trifluoroethyl)amino]-2-chloro-3-methyl-benzonitrile(compound 119);cis-2,5-Dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine(compound 120);trans-2,5-dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine(compound 121);1-(4-Nitro-3-trifluoromethylphenyl)-piperidine-2-carboxylic acid ethylester (compound 122);1-(4-Nitro-3-trifluoromethylphenyl)-4-(hydroxymethyl)-piperidine(compound 123);(1-(3-trifluoromethyl-4-nitrophenyl)piperidin-2-yl)methyl acetate(compound 124); 4-(2-Hydroxymethyl-pyrrolidin-1-yl)-benzonitrile(compound 125);4-Benzyl-2-hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine(compound 126);2-Fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-benzonitrile (compound127); 4-Hydroxy-1-(4-nitrophenyl)-pyrrolidine-2-carboxylic acid ethylester (compound 128);4-Hydroxy-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine-2-carboxylicacid ethyl ester (compound 129);5-Hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidin-3-ol(compound 130);2-(Aminomethyl)-1-(4-Nitro-3-trifluoromethylphenyl)-pyrrolidine(compound 131); 4-Hydroxy-1-(4-nitrophenyl)-pyrrolidine-2-carboxylicacid (compound 132); and4-Hydroxy-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine-2-carboxylicacid (compound 133); and pharmaceutically acceptable salts, esters,amides, and prodrugs thereof.
 63. The compound of claim 1, wherein thecompound is a selective androgen receptor modulator.
 64. The selectiveandrogen receptor modulator of claim 63, wherein the compound is anandrogen receptor agonist.
 65. The selective androgen receptor modulatorof claim 63, wherein the compound is an androgen receptor antagonist.66. The selective androgen receptor modulator of claim 63, wherein thecompound is an androgen receptor partial agonist.
 67. The selectiveandrogen receptor modulator of claim 63, wherein the compound is atissue-specific modulator.
 68. The compound of claim 1, wherein thecompound is a selective androgen binding compound.
 69. A method formodulating an activity of an androgen receptor, comprising contacting anandrogen receptor with a compound of claim
 1. 70. The method of claim68, wherein the androgen receptor is in a cell.
 71. A method foridentifying a compound that modulates an activity of an androgenreceptor comprising: contacting a cell expressing an androgen receptorwith a compound of claim 1; and monitoring an effect of the compoundupon the cell.
 72. A method for treating a patient having a conditionsusceptible to treatment with an androgen receptor modulator, comprisingadministering to the patient a pharmaceutical agent comprising acompound of claim
 1. 73. The method of claim 72, wherein the conditionis selected from among maintenance of muscle strength and function;reversal or prevention of frailty or age-related functional decline inthe elderly; treatment of catabolic side effects of glucocorticoids;treatment of reduced bone mass, density or growth; treatment of chronicfatigue syndrome; chronic myalgia; treatment of acute fatigue syndromeand muscle loss; accelerating of wound healing; accelerating bonefracture repair; accelerating healing of complicated fractures; in jointreplacement; prevention of post-surgical adhesion formation;acceleration of tooth repair or growth; maintenance of sensory function;treatment of periodontal disease; treatment of wasting secondary tofractures and treatment of wasting in connection with chronicobstructive pulmonary disease, treatment of wasting in connection withchronic liver disease, treatment of wasting in connection with AIDS,cancer cachexia, burn and trauma recovery, chronic catabolic state,eating disorders and chemotherapy; treatment of cardiomyopathy;treatment of thrombocytopenia; treatment of growth retardation inconnection with Crohn's disease; treatment of short bowel syndrome;treatment of irritable bowel syndrome; treatment of inflammatory boweldisease; treatment of Crohn's disease and ulcerative colitis; treatmentof complications associated with transplantation; treatment ofphysiological short stature including growth hormone deficient childrenand short stature associated with chronic illness; treatment of obesityand growth retardation associated with obesity; treatment of anorexia;treatment of hypercortisolism and Cushing's syndrome; Paget's disease;treatment of osteoarthritis; induction of pulsatile growth hormonerelease; treatment of osteochondro-dysplasias; treatment of depression,nervousness, irritability and stress; treatment of reduced mental energyand low self-esteem; improvement of cognitive function; treatment ofcatabolism in connection with pulmonary dysfunction and ventilatordependency; treatment of cardiac dysfunction; lowering blood pressure;protection against ventricular dysfunction or prevention of reperfusionevents; treatment of adults in chronic dialysis; reversal or slowing ofthe catabolic state of aging; attenuation or reversal of proteincatabolic responses following trauma; reducing cachexia and protein lossdue to chronic illness; treatment of hyper-insulinemia; treatment ofimmunosuppressed patients; treatment of wasting in connection withmultiple sclerosis or other neurodegenerative disorders; promotion ofmyelin repair; maintenance of skin thickness; treatment of metabolichomeostasis and renal homeostasis; stimulation of osteoblasts, boneremodeling and cartilage growth; regulation of food intake; treatment ofinsulin resistance; treatment of insulin resistance in the heart;treatment of hypothermia; treatment of congestive heart failure;treatment of lipodystrophy; treatment of muscular atrophy; treatment ofmusculoskeletal impairment; improvement of the overall pulmonaryfunction; treatment of sleep disorders; and the treatment of thecatabolic state of prolonged critical illness; treatment of hirsutism,acne, seborrhea, androgenic alopecia, anemia, hyperpilosity, benignprostate hypertrophy, adenomas and neoplasies of the prostate andmalignant tumor cells containing the androgen receptor; osteosarcoma;hypercalcemia of malignancy; metastatic bone disease; treatment ofspermatogenesis, endometriosis and polycystic ovary syndrome;counteracting preeclampsia, eclampsia of pregnancy and preterm labor;treatment of premenstrual syndrome; treatment of vaginal dryness; agerelated decreased testosterone levels in men, male menopause,hypogonadism, male hormone replacement, male and female sexualdysfunction, male and female contraception, hair loss, Reaven's Syndromeand the enhancement of bone and muscle strength.
 74. A method accordingto claim 72, wherein the patient has a condition selected from amongacne, male-pattern baldness, wasting diseases, hirsutism, hypogonadism,osteoporoses, infertility, impotence and cancer.
 75. A method forstimulating hematopoiesis in a patient, comprising administering to thepatient a pharmaceutical agent comprising a compound of claim
 1. 76. Amethod of contraception, comprising administering to a patient apharmaceutical agent comprising a compound of claim
 1. 77. A method ofimproving athletic performance in an athlete, comprising administeringto the athlete a pharmaceutical agent comprising a compound of claim 1.78. A pharmaceutical composition, comprising a compound of claim 1 and apharmaceutically acceptable carrier. 79-81. (canceled)
 82. An article ofmanufacture, comprising: packaging material; a compound of claim 1 thatis effective for modulating the activity of androgen receptor, or fortreatment, prevention or amelioration of one or more symptoms ofandrogen receptor mediated diseases or disorders, or diseases ordisorders in which androgen receptor activity is implicated, within thepackaging material; and a label that indicates that the compound orcomposition, or pharmaceutically acceptable derivative thereof, is usedfor modulating the activity of androgen receptor or for treatment,prevention or amelioration of one or more symptoms of androgen receptormediated diseases or disorders, or diseases or disorders in whichandrogen receptor activity is implicated.